EP1456182B1 - Pyrimidine derivatives as modulators of insuline-like growth factor-1 receptor (igf-i) - Google Patents

Pyrimidine derivatives as modulators of insuline-like growth factor-1 receptor (igf-i) Download PDF

Info

Publication number
EP1456182B1
EP1456182B1 EP02791165A EP02791165A EP1456182B1 EP 1456182 B1 EP1456182 B1 EP 1456182B1 EP 02791165 A EP02791165 A EP 02791165A EP 02791165 A EP02791165 A EP 02791165A EP 1456182 B1 EP1456182 B1 EP 1456182B1
Authority
EP
European Patent Office
Prior art keywords
pyrimidine
ylamino
pyrazol
alkyl
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP02791165A
Other languages
German (de)
French (fr)
Other versions
EP1456182A1 (en
Inventor
Bernard AstraZeneca Res. Centre Reims BARLAAM
Andrew AstraZeneca R & D Alderley PAPE
Andrew AstraZeneca R & D Alderley THOMAS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to SI200230824T priority Critical patent/SI1456182T1/en
Publication of EP1456182A1 publication Critical patent/EP1456182A1/en
Application granted granted Critical
Publication of EP1456182B1 publication Critical patent/EP1456182B1/en
Priority to CY20091100558T priority patent/CY1109101T1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to pyrimidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
  • the insulin-like growth factor (IGF) axis consists of ligands, receptors, binding proteins and proteases.
  • the two ligands, IGF-I and IGF-II are mitogenic peptides that signal through interaction with the type 1 insulin-like growth factor receptor (IGF-1R), a hetero-tetrameric cell surface receptor.
  • IGF-1R insulin-like growth factor receptor
  • Binding of either ligand stimulates activation of a tyrosine kinase domain in the intracellular region of the ⁇ -chain and results in phosphorylation of several tyrosine residues resulting in the recruitment and activation of various signaling molecules.
  • the intracellular domain has been shown to transmit signals for mitogenesis, survival, transformation, and differentiation in cells.
  • the structure and function of the IGF-1R has been reviewed by Adams et al (Cellular and Molecular Life Sciences, 57, 1050-1093, 2000 ).
  • the IGF-IIR also known as mannose 6-phosphate receptor
  • the IGF binding proteins (IGFBP) control availability of circulating IGF and release of IGF from these can be mediated by proteolytic cleavage.
  • IGFBP IGF binding proteins
  • IGF interleukin-1
  • IGF-IIR Upregulation of components of the IGF axis has been described in various tumour cell lines and tissues, particularly tumours of the breast ( Surmacz, Journal of Mammary Gland Biology & Neoplasia, 5, 95-105, 2000 ), prostate ( Djavan et al, World J. Urol., 19, 225-233, 2001 , and O'Brien et al, Urology, 58, 1-7, 2001 ) and colon ( Guo et al, Gastroenterology, 102, 1101-1108, 1992 ). Conversely, IGF-IIR has been implicated as a tumour suppressor and is deleted in some cancers ( DaCosta et al, Journal of Mammary Gland Biology & Neoplasia, 5, 85-94, 2000 ).
  • Antisense oligonucleotides have shown that inhibition of IGF-1R expression results in induction of apoptosis in cells in vivo ( Resnicoff et al, Cancer Res., 55, 2463-2469, 1995 ) and have been taken into man ( Resnicoff et al, Proc. Amer. Assoc. Cancer Res., 40 Abs 4816, 1999 ). However, none of these approaches is particularly attractive for the treatment of major solid tumour disease.
  • IGF-1R tyrosine kinase domain is an appropriate therapy by which to treat cancer.
  • IGF-1R tyrosine kinase domain is an appropriate therapy by which to treat cancer.
  • IGF-1R tyrosine kinase domain is an appropriate therapy by which to treat cancer.
  • a point mutation in the ATP binding site which blocks receptor tyrosine kinase activity has proved effective in preventing tumour cell growth ( Kulik et al, Mol. Cell. Biol., 17, 1595-1606, 1997 ).
  • R 1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino (-NH 2 ), hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR 5 R 6 , carboxyl, hydroxyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, phenylcarbonyl, -S(O) m C 1 -C 6 alkyl, -
  • an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched.
  • R 5 and R 6 , or R 7 and R 8 , or R 7a and R 8a , or R 9 and R 10 , or R 11 and R 12 , or R 11a and R 12a , or R 13 and R 14 , or R 15 and R 16 , or R 15a and R 16a represent a saturated heterocycle
  • the only heteroatom present is the nitrogen atom to-which R 5 and R 6 , or R 7 and R 8 , or R 7a and R 8a , or R 9 and R 10 , or R 11 and R 12 or R 11a and 2 12a , or R 13 and R 14 , or R 15 and R 16 , or R 15a and R 16a are attached.
  • R 1 it should be noted that the unsaturated 5- to 6-membered ring may have alicyclic or aromatic properties.
  • Examples of “C 1 -C 6 alkyl” and “C 1 -C 4 alkyl” include methyl, ethyl, isopropyl and t -butyl.
  • Examples of “C 1 -C 6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t -butoxycarbonyl.
  • Examples of “C 1 -C 6 alkoxy” and “C 1 -C 3 alkoxy” include methoxy, ethoxy and propoxy.
  • Examples of “C 1 -C 6 alkylcarbonylamino” include formamido, acetamido and propionylamino.
  • Examples of "S(O) m C 1 -C 6 alkyl” wherein m is 0 to 2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl
  • Examples of "C 1- C 6 alkylcarbonyl” include propionyl and acetyl.
  • Examples of “C 2 -C 6 alkenyl” are vinyl, allyl and 1-propenyl.
  • Examples of “C 3 -C 6 cycloalkyl” are cyclopropyl, cyclopentyl and cyclohexyl.
  • a "5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur” is a fully unsaturated, aromatic monocyclic ring containing 5 or 6 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which may, unless otherwise specified, be carbon or nitrogen linked.
  • a "5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur” is pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl; pyrrolyl or thienyl.
  • an "unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur” is a fully or partially unsaturated, monocyclic ring containing 5 or 6 atoms optionally of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, and which may, unless otherwise specified, be carbon or nitrogen linked.
  • an "unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur” is phenyl or pyridyl.
  • a "5- membered heteroaromatic ring comprising art least one ring heteroatom selected from nitrogen, oxygen and sulphur" is a fully unsaturated, aromatic monocyclic ring containing 5 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which may, unless otherwise specified, be carbon or nitrogen linked.
  • a "5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur” is pyrazolyl.
  • R 1 represents an optionally substituted 5- or 6-membered heteroaromatic ring comprising at least-one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur.
  • heteroaromatic rings include thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2-or 3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g.
  • pyrazinyl e.g. 2-pyrazinyl
  • pyridazinyl e.g. 3-pyridazinyl
  • pyrimidinyl e.g. 4- or 5-pyrimidinyl
  • pyridyl e.g. 2-, 3- or 4-pyridyl
  • the 5- or 6-membered heteroaromatic ring is optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from C 1 -C 6 , particularly C 1 -C 4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, - tert-butyl, n-pentyl or n-hexyl), C 1 -C 6 , particularly C 1 -C 4 alkoxy-(such as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, n-pentoxy or n-hexoxy) (each of the C 1 -C 6 alkyl and C 1 -C 6 alkoxy substituent groups being optionally substituted by at least one substituent, e.g.
  • halogen such as fluorine, chlorine bromine or iodine
  • amino such as hydroxyl and trifluoromethyl
  • halogen such as fluorine, chlorine, bromine or iodine
  • nitro, cyano, -NR 5 R 6 carboxyl, hydroxyl, C 2 -C 6 , particularly C 2 -C 4 alkenyl (such as ethenyl), C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C 1 -C 6 , particularly C 1 -C 4 alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C 1 -C 6 , particularly C 1 -C a alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbon
  • Examples of the unsaturated 5- to 6-membered ring include phenyl, cylopentenyl, cyclohexenyl, thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2- or 3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl), pyrazinyl (e.g. 2-pyrazinyl), pyridazinyl (e.g.
  • 3-pyridazinyl pyrimidinyl (e.g. 4- or 5-pyrimidinyl) and pyridyl (2-, 3- or 4-pyridyl).
  • the ring may itself be optionally substituted by at least one substituent (e.g.
  • C 1 -C 6 particularly C 1 -C 4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-penty) or n-hexyl), C 1 -C 6 , particularly C 1 -C 4 alkoxy (such as methoxy, ethoxy, n-propoxy; n-butoxy, tert -butoxy, n-pentoxy or n-hexoxy) (each of the C 1 -C 6 alkyl and C 1 -C 6 alkoxy-substituent groups being optionally substituted by at least one substituent, e.g.
  • halogen such as fluorine, chlorine bromine or iodine
  • amino such as hydroxyl and trifluoromethyl
  • halogen such as fluorine, chlorine, bromine or iodine
  • nitro, cyano, -NR 9 R 10 carboxyl, hydroxyl, C 2 -C 6 , particularly C 2 -C 4 alkenyl (such as ethenyl), C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C 1 -C 6 , particularly C 1 -C 4 alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C 1 -C 6 , particularly C 1 -C 4 alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbony
  • R 1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, nitro, cyano, -NR 5 R 6 , carboxyl, hydroxyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, phenylcarbonyl, -S(O) m C 1 -C 6 alkyl, -C(O)NR 7 R 8 , -SO 2 NR 7a R 8a , and an unsaturated 6-membered ring which may comprise one ring nitrogen atom, the ring itself being optionally substituted by at least one substituent
  • R 1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, phenyl and pyridyl, each of the phenyl and pyridyl substituent groups itself being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen.
  • R 1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen; oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy (each of which may be optionally substituted by at least one substituent selected from hydroxyl), halogen, -C(O)NR 7 R 8 , C 1 -C 6 alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen and oxygen, the ring itself being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen), halogen and cyano; wherein R 7 and R 8 are both hydrogen or R 7 and R 8 together with the nitrogen atom to which they are attached form a 4-
  • R 1 represents pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl or thienyl; said pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl and thienyl being optionally substituted by at least one substituent selected from methyl, isopropyl, hydroxymethyl, methoxy, chloro, bromo, carbamoyl, methoxycarbonyl, pyrrolidin-1-ylcarbonyl, phenyl and pyridyl; said phenyl or pyridyl being optionally substituted by at least one substituent selected from methyl, trifluoromethyl, methoxy, ethoxy,
  • R 1 represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid-5-yl, 2-cyanopyrid-5-yl, 3-bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-yl, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-yl, 6-methylpyrid-2-yl, 5,6-dimethylpyrid-2-yl, imidazol-4-yl, imidazol-5-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl, 3-methoxycarbonylisoxazol-5-yl, 3-(hydroxymethyl)isoxazol-5-yl, 3-carbamoylisoxazol
  • R 2 represents a C 1 -C 4 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl and C 1 -C 3 alkoxy (e.g. methoxy, ethoxy and n-propoxy).
  • substituent e.g. one, two, three or four substituents independently
  • halogen e.g. fluorine, chlorine, bromine or iodine
  • hydroxyl e.g. methoxy, ethoxy and n-propoxy
  • R 2 represents CH 2 or (CH 2 ) 2 .
  • R 2 represents a C 1 -C 4 alkyl group.
  • R 2 represents methyl, ethyl and propyl.
  • R 3 represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine) or trifluoromethyl.
  • R 3 represents chlorine or bromine.
  • R 3 represents hydrogen or halogen.
  • R 3 represents hydrogen, chloro or bromo.
  • R 4 represents an optionally substituted 5-membered heteroaromatic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur.
  • rings include thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2- or 3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl).
  • thienyl e.g. 3-thienyl
  • pyrazolyl e.g. 4-pyrazolyl
  • isoxazolyl e.g. 5-isoxazolyl
  • thiadiazolyl e.g. 2-pyrrolyl
  • the 5-membered heteroaromatic ring in R 4 is optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from C 1 -C 6 , particularly C 1 -C 4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert -butyl, n-pentyl or n-hexyl), C 1 -C 6 , particularly C 1 -C 4 alkoxy (such as methoxy, ethoxy, n-propoxy, n-butoxy, tert -butoxy, n-pentoxy or n-hexoxy) (each of the C 1 -C 6 alkyl and C 1 -C 6 alkoxy-substituent groups being optionally substituted by at least one substituent, e.g.
  • halogen such as fluorine, chlorine bromine or iodine
  • amino such as hydroxyl and trifluoromethyl
  • halogen such as fluorine, chlorine, bromine or iodine
  • nitro cyano, -NR 13 R 14 , carboxyl, hydroxyl, C 2 -C 6 , particularly C 2 -C 4 alkenyl (such as ethenyl), C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C 1 -C 4 , particularly C 1 -C 3 alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C 1 -C 4 , particularly C 1 -C 3 alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbony
  • R 4 represents a 5-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen,-the ring being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, nitro, cyano, -NR 13 R 14 , carboxyl, hydroxyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, phenylearbonyl, -S(O) p C 1 -C 4 alkyl, -C(O)NR 15 R 16 and -SO 2 NR 15a R 16a .
  • R 4 represents a 5-membered heteroaromatic ring comprising two ring nitrogen atoms, the ring being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen and C 3 -C 6 cycloalkyl.
  • R 4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, the ring being optionally substituted by at least one substituent selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl.
  • R 4 represents pyrazolyl, the ring being optionally substituted by at least one substituent selected from methyl, ethyl, isopropyl, propyl, t -butyl and cyclopropyl.
  • R 4 represents 5-methylpyrazol-3-yl, 5-ethylpyrazol-3-yl, 5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl, 5- t -butylpyrazol-3-yl and 5-cyclopropylpyrazol-3-yl.
  • R 5 and R 6 each independently represent hydrogen, C 1 -C 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl and
  • R 7 and R 8 each independently represent hydrogen, C 1 -C- 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 7 and R 8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl
  • R 7a and R 8a each independently represent hydrogen, C 1 -C 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 7a and R 8a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopen
  • R 9 and R 10 each independently represent hydrogen, C 1 -C 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl and
  • R 11 and R 12 each independently represent hydrogen, C 1 -C 4 , particularly C 1- C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl cyclopentyl and cyclohexyl), or R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1- C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl cyclopentyl and cyclohexy
  • R 11a and R 12a each independently represent hydrogen, C 1 -C 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 11a and R 12a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopen
  • R 13 and R 14 each independently represent hydrogen, C 1 -C 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl and
  • R 15 and R 16 each independently represent hydrogen, C 1 -C 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 15 and R 16 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl and
  • R 15a and R 16a each independently represent hydrogen, C 1 -C 4 , particularly C 1 -C 2 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl) or C 3 -C 6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R 15a and R 16a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • C 1 -C 2 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl
  • C 3 -C 6 cycloalkyl cyclopropyl, cyclobutyl, cyclopen
  • Examples of compounds of the invention include:
  • particular compounds of the invention are any one of Examples 3, 5, 8, 9, 11, 12, 34, 39, 40, 41, 47, 48, 68, 70 and 79 or pharmaceutically acceptable salts and solvates of any one thereof.
  • particular compounds of the invention are any one of the Examples or pharmaceutically acceptable salts and solvates of any one thereof.
  • the present invention further provides a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, which comprises:
  • Process (iii) may conveniently be carried out in a suitable solvent such as N -methylpyrrolidinone or butanol at a temperature in the range from 100-200°C, in particular in the range from 150-170°C.
  • a suitable base such as, for example, sodium methoxide or potassium carbonate.
  • Process (iv) may be carried out in a suitable solvent, for example, an alcohol such as methanol or butanol at a temperature in the range from 50-120°C, in particular in the range from 70-100°C.
  • a suitable solvent for example, an alcohol such as methanol or butanol at a temperature in the range from 50-120°C, in particular in the range from 70-100°C.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid; the introduction of an acyl group using, for example, an acryl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • reduction reactions include the reduction of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating; and particular examples of oxidation reactions include oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p -toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p -toluenesulphonate
  • an alkali metal salt such as a sodium or potassium salt.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. For example where R 4 is pyrazolyl; pyraxolyl-5-yl and pyrazolyl-3-y] are tautomers of the same compound.
  • the compounds of formula (I) have activity as pharmaceuticals, in particular as modulators or inhibitors of insulin-like growth factor-1 receptor (IGF-1R) activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers:
  • the compounds of the invention are especially useful in the treatment of tumors of the breast and prostate.
  • the present invention provides a compound of formula (I) , or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy,
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the invention also provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • the invention still further provides a method of modulating insulin-like growth factor-1 receptor (IGF-1R) activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • IGF-1R insulin-like growth factor-1 receptor
  • the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is-in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • lubricating agents
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example..sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the size of the dose for therapeutic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a compound of the invention will be administered so that a daily dose in the range, for example, from 0.5 mg to 75 mg active ingredient per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used.
  • a dose in the range for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used.
  • Oral administration is however preferred.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient.
  • the starting materials for the examples above are either commercially available or are readily prepared by standard methods from known materials.
  • the following reactions are an illustration, but not a limitation, of some of the starting materials used in the above reactions.
  • Acetonitrile (13.7ml, 260mmol) was added to a suspension of sodium hydride (10.4g of a 60% suspension in mineral oil, 260mmol) in ethyl propionate (22.3g, 220mmol) and anhydrous 1,4-dioxane (200ml) at ambient temperature. The mixture was heated at 100°C for 12 hours and then allowed to cool. Water was added, the mixture adjusted to pH 2.0 with concentrated hydrochloric acid and extracted with DCM. The extracts were combined dried (MgSO 4 ) and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with DCM to give the title compound (20g, 94%) as an oil. NMR (CDCl 3 ): 1.10 (t, 3H), 2.65 (q, 2H), 3.50 (s, 2H).
  • N-chlorosuccinimide (5.50g, 41.3mmol) was added in portions to a solution of benzaldehyde oxime (5.0g, 41.3mmol) in DMF (34ml) such that the temperature did not rise above 35°C. The mixture was stirred at ambient temperature for 2 hours and then cooled witch an ice bath. Water was added and the aqueous mixture extracted with ether. The organics were combined, washed with water and brine, dried (MgSO 4 ) and the solvent removed by evaporation to give the title compound (6.43g, 100%) as an oil. NMR (CDCl 3 ): 7.4 (m, 3H), 7.8 (d, 2H), 8.9 (bs, 1H).
  • ⁇ -Chloro-pyrid-3-ylcarbaldehyde oxime was prepared according to the method described in Tetrahedron 2000, 56, 1057-1064 .
  • Trifluoroacetic acid (1.7ml, 2.6mmol) was added dropwise to a solution of 5-( tert- butoxycarbonylaminomethyl)-3-phenylisoxazole (Method 43; 473mg, 1.73mmol) in DCM (8ml) cooled in an ice bath. The mixture was warmed to ambient temperature and stirred for 18 hours and the volatiles removed by evaporation. The residue was triturated with ether to give the title compound (427mg, 86%). NMR (DMSO) 4.33 (s, 2H), 7.1 (s, 1H), 7.5 (m, 3H), 7.8 (m, 2H), 8.6 (br s, 3H).
  • Trifluoroacetic acid (2.1 ml, 29mmol) was added to a solution of 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 790mg, 2.9mmol) in DCM (15ml). The mixture was stirred at ambient temperature for 4 hours then the volatiles removed by evaporation. The residue was triturated with diethyl ether to give the title compound (763g, 93%). NMR (DMSO): 1.31 (t, 3H), 4.37 (m, 2H), 6.97 (s, 1H), 8.64 (s, 3H); m/z 171 (MH) + .
  • Trifluoroacetic acid (4ml, 54mmol) was added to a solution of 3-hydroxymethyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 75; 1.25g, 5.4mmol) in DCM (40ml). The mixture was stirred at ambient temperature for 18 hours then the volatiles removed by evaporation. The residue was purified by chromatography on a SCX-2 column (50g) eluting with methanol then 7N ammonia in methanol to give the title compound (676mg, 96%). NMR (DMSO): 1.97 (br s, 2H), 3.76 (s, 2H), 4.44 (s, 2H), 5.38 (s, 1H), 6.26 (s, 1H).
  • Copper (I) cyanide (2.49g, 27.8mmol), tetra-n-butylammoniumcyanide (1.87g, 6.95mmol), tris(dibenzylideneacetone)dipalladium(0) (0.247g, 0.28mmol) and diphenylphosphinoferrocene (0.619g, 1.12mmol) were added to a degassed solution of 5-[N-( tert -butoxycarbonyl)aminomethyl]-3-(2-iodoophenyl)isoxazole (Method 79; 2.78g, 6.95mmol) in 1,4-dioxan (35ml) under nitrogen.
  • Trifluoroacetic acid (2.5ml, 3.8mmol) was added dropwise to a solution of 3-methyl-5- ⁇ 2-[ bis -(N- tert -butoxycarbonyl)amino]ethyl ⁇ isoxazole (Method 82; 0.589g, 1.8mmol) in DCM (10ml) cooled at 0°C. The mixture was allowed to warm to ambient temperature and stirred for 48 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on a SCX-2 ion exchange column eluting with methanol and then 7 N ammonia in methanol.
  • Trimethylsilylcyanide (1.9ml, 14.5mmol) was added dropwise to a suspension of 2-(N-oxopyridin-4-yl)pyridine (Method 98; 1g, 5.8mmol) and triethylamine (1.2ml, 8.7mmol) in acetonitrile (5ml). The mixture was heated at 110°C for 18 hours, cooled to ambient temperature then diluted with aqueous saturated sodium hydrogen carbonate solution. The mixture was extracted with DCM, the extracts dried (MgSO 4 ) and the volatiles removed by evaporation.
  • 2-(3-Bromopyridin-5-yl)pyridine (2g, 10.9mmol) in THF (10ml) was added dropwise to a solution of 2-pyridylzincbromide (22ml of a 0.5M solution in THF, 11 mmol) in THF (10ml) under a nitrogen atmosphere.
  • Tetrakis (triphenylphosphine)palladium(0) (630mg, 0.54mmol) was added and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride solution then the volatiles were removed by evaporation. The residue was suspended in water then extracted with DCM.
  • the pFastBac-1 vector containing GST-IGFR was transformed into E. coli DH10Bac cells containing the baculovirus genome (bacmid DNA) and via a transposition event in the cells, a region of the pFastBac vector containing gentamycin resistance gene and the GST-IGFR expression cassette including the baculovirus polyhedrin promoter was transposed directly into the bacmid DNA.
  • gentamycin, kanamycin, tetracycline and X-gal resultant white colonies should contain recombinant bacmid DNA encoding GST-IGFR.
  • Bacmid DNA was extracted from a small scale culture of several BH10Bac white colonies and transfected into Spodoptera frugiperda Sf21 cells grown in TC100 medium (Life Technologies Ltd, UK) containing 10% serum using CellFECTIN reagent (Life Technologies Ltd, UK) following the manufacturer's instructions.
  • Virus particles were harvested by collecting cell culture medium 72 hrs post transfection. 0.5 mls of medium was used to infect 100 ml suspension culture of Sf21s containing 1 x 10 7 cells/ml. Cell culture medium was harvested 48 hrs post infection and virus titre determined using a standard plaque assay procedure. Virus stocks were used to infect Sf9 and "High 5" cells at a multiplicity of infection (MOI) of 3 to ascertain expression of recombinant GST-IGFR.
  • MOI multiplicity of infection
  • the GST-IGFR protein was purified by affinity chromatography on Glutathione-Sepharose followed by elution with glutathione. Briefly, cells were lysed in 50mM HEPES pH 7.5 (Sigma, H3375), 200mM NaCl (Sigma, S7653), Complete Protease Inhibitor cocktail (Roche, 1 873 580) and 1mM DTT (Sigma, D9779), hereinafter referred to as lysis buffer. Clarified lysate supernatant was loaded through a chromatography column packed with Glutathione Sepharose (Amersham Pharmacia Biotech UK Ltd.). Contaminants were washed from the matrix with lysis buffer until the UV absorbance at 280nm returned to the baseline.
  • lysis buffer containing 20mM reduced glutathione (Sigma, D2804) and fractions containing the GST fusion protein were pooled and dialysed into a glycerol-containing buffer comprising 50 mM HEPES, pH 7.5, 200 mM NaCl, 10% glycerol (v/v), 3 mM reduced glutathione and 1 mM DTT.
  • the activity of the purified enzyme was measured by phosphorylation of a synthetic poly GluAlaTyr (EAY) 6:3:1 peptide (Sigma-Aldrich Company Ltd, UK, P3899) using an ELISA detection system in a 96-well format
  • GST-IGF-1R fusion protein at 75ng/ml in 100mM HEPES, pH 7.4, 5mM DTT, 0.25mM Na 3 VO 4 , 0.25% Triton X-100, 0.25mg/ml BSA, freshly prepared.
  • Anti-phosphotyrosine antibody monoclonal from Upstate Biotechnology Inc., NY, USA (UBI 05-321). Dilute 3 ⁇ l in 11 ml PBS/T + 0.5% BSA per assay plate.
  • Sheep- anti-mouse IgG HRP-conjugated secondary antibody from Amersham Pharmacia Biotech UK Ltd. (NXA931). Dilute 20 ⁇ l of stock into 11 ml PBS/T + 0.5% BSA per assay plate.
  • Stop solution is 1M H 2 SO 4 (Fisher Scientific UK. Cat. No. S/9200/PB08).
  • the poly EAY substrate was diluted to 1 ⁇ g/ml in PBS and then dispensed in an amount of 100 ⁇ l per well into a 96-well plate. The plate was sealed and incubated overnight at 4°C. Excess poly EAY solution was discarded and the plate was washed (2x PBS/.T; 250 ⁇ l PBS per well), blotting dry between washes. The plate was then washed again (1x 50mM HEPES, pH.7.4; 250 ⁇ l per well) and blotted dry (this is important in order to remove background phosphate levels). 100 ⁇ l test compound solution was added with 40 ⁇ l of kinase solution to each well. Then 50 ⁇ l of co-factor solution were added to each well and the plate was incubated for 60 minutes at room temperature.
  • the plate was emptied (i.e. the contents were discarded) and was washed twice with PBS/T (250 ⁇ l per well), blotting dry between each wash. 100 ⁇ l of diluted anti-phosphotyrosine antibody were added per well and the plate was incubated for 60 minutes at room temperature.
  • the plate was again emptied and washed twice with PBS/T (250 ⁇ l per well), blotting dry between each wash. 100 ⁇ l of diluted sheep- anti-mouse IgG antibody were added per well and the plate was left for 60 minutes at room temperature. The contents were discarded and the plate washed twice with PBS/T (250 ⁇ l per well), blotting dry between each wash. 100 ⁇ l of TMB solution were added per well and the plate was incubated for 5-10 minutes at room temperature (solution turns blue in the presence horse radish peroxidase).
  • the compounds of the Examples were found to have an IC 50 in the above test of less than 100 ⁇ M.
  • Exponentially growing NIH3T3/IGFR cells were harvested and seeded in complete growth medium into a flat-bottomed 96 well tissue culture grade plate (Costar 3525) at 1.2x 10 4 cells per well in a volume of 100 ⁇ l.
  • the compounds of the Examples were found to have an IC 50 in the above test of less than 50 ⁇ M.
  • IGF-IR mediated signal transduction was determined by measuring changes in phosphorylation of IGF-IR, Akt and MAPK (ERK1 and 2) in response to IGF-I stimulation of MCF-7 cells (ATCC No. HTB-22). A measure of selectivity was provided by the effect on MAPK phosphorylation in response to EGF in the same cell line.
  • Mouse anti-actin clone AC-40 (Sigma-Aldrich Company Ltd, UK, A4700) Antibody dilutions Antibody Dilution in PBST Secondary antibody in PBST IGFR 1:200 with 5% milk Anti-rabbit with 5% milk Phospho-IGFR 1:1000 with 5% milk Anti-rabbit with 5% milk Akt 1:1000 with 5% milk Anti-mouse with 5% milk PhosphoAkt 1:1000 with 5% milk Anti-rabbit with 5% milk MAPK 1:1000 with 5% milk Anti-rabbit with 5% milk Phospho-MAPK 1:1000 with 5% milk Anti-rabbit with 5% milk Actin 1:1000 with 5% milk Anti-mouse with 5% milk
  • MCF-7 cells were plated out in a 24 well plate at 1x 10 5 cells/well in 1ml complete growth medium. The plate was incubated four 24 hours to allow the cells to settle. The medium was removed and the plate was washed gently 3 times with PBS 2ml/well. 1ml of starvation medium was added to each well and the plate was incubated for 24 hours to serum starve the cells.
  • a pipette was used to repeatedly draw up and expel the Laemmli buffer/cell mix and transfer into a 1.5ml Eppendorf tube.
  • the harvested cell lysates were kept at -20°C until required.
  • the protein concentration of each lysate could be determined using the DC protein assay kit (Bio-Rad Laboratories, USA, according to manufacturer's instructions).
  • the blotted membranes were stained with 0.1% Ponceau S to visualise transferred proteins and then cut into strips horizontally for multiple antibody incubations according to the molecular weight standards. Separate strips were used for detection of IGF-1R, Akt, MAPK and actin control.
  • the membranes were blocked for 1 hour at room temperature in PBST + 5% milk solution. The membranes were then placed into 3ml primary antibody solution in 4 well plates and the plates were incubated overnight at 4°C. The membranes were washed in 5ml PBST, 3 times for 5 minutes each wash. The HRP-conjugated secondary antibody solution was prepared and 5ml was added per membrane. The membranes were incubated for 1 hour at room temperature with agitation. The membranes were washed in 5ml PBST, 3 times for 5 minutes each wash. The ECL solution (supersignal ECL, Pierce, Perbio Science UK Ltd) was prepared and incubated with the membranes for 1 minute (according to manufacturer's instructions), followed by exposure to light sensitive film and development.
  • ECL solution supersignal ECL, Pierce, Perbio Science UK Ltd
  • the compounds of the Examples were found to have an IC 50 in the above test of lessthan 20 ⁇ M.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention provides compounds of formula [Chemical formula should be inserted here. Please see paper copy]in which R1, R2, R3 and R4 have the meanings defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy.

Description

  • The present invention relates to pyrimidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
  • The insulin-like growth factor (IGF) axis consists of ligands, receptors, binding proteins and proteases. The two ligands, IGF-I and IGF-II, are mitogenic peptides that signal through interaction with the type 1 insulin-like growth factor receptor (IGF-1R), a hetero-tetrameric cell surface receptor. Binding of either ligand stimulates activation of a tyrosine kinase domain in the intracellular region of the β-chain and results in phosphorylation of several tyrosine residues resulting in the recruitment and activation of various signaling molecules. The intracellular domain has been shown to transmit signals for mitogenesis, survival, transformation, and differentiation in cells. The structure and function of the IGF-1R has been reviewed by Adams et al (Cellular and Molecular Life Sciences, 57, 1050-1093, 2000). The IGF-IIR (also known as mannose 6-phosphate receptor) has no such kinase domain and does not signal mitogenesis but may act to regulate ligand availability at the cell surface, counteracting the effect of the IGF-1R. The IGF binding proteins (IGFBP) control availability of circulating IGF and release of IGF from these can be mediated by proteolytic cleavage. These other components of the IGF axis have been reviewed by Collett-Solberg and Cohen (Endocrine, 12, 121-136, 2000).
  • There is considerable evidence linking IGF signaling with cellular transformation and the onset and progression of tumours. IGF has been identified as the major survival factor that protects from oncogene induced cell death (Harrington et al, EMBO J, 13, 3286-3295, 1994). Cells lacking IGF-IR have been shown to be refractory to transformation by several different oncogenes (including SV40T antigen and ras) that efficiently transform corresponding wild-type.cells (Sell et al., Mol. Cell Biol., 14, 3604-12,1994). Upregulation of components of the IGF axis has been described in various tumour cell lines and tissues, particularly tumours of the breast (Surmacz, Journal of Mammary Gland Biology & Neoplasia, 5, 95-105, 2000), prostate (Djavan et al, World J. Urol., 19, 225-233, 2001, and O'Brien et al, Urology, 58, 1-7, 2001) and colon (Guo et al, Gastroenterology, 102, 1101-1108, 1992). Conversely, IGF-IIR has been implicated as a tumour suppressor and is deleted in some cancers (DaCosta et al, Journal of Mammary Gland Biology & Neoplasia, 5, 85-94, 2000). There is a growing number of epidemiological studies linking increased circulating IGF (or increased ratio of IGF-1 to IGFBP3) with cancer risk (Yu and Rohan, J. Natl. Cancer Inst. , 92, 1472-1489, 2000). Transgenic mouse models also implicate IGF signaling in the onset of tumour cell proliferation (Lamm and Christofori, Cancer Res. 58, 801-807, 1998, Foster et al, Cancer Metas. Rev., 17, 317-324, 1998,-and DiGiovanni et al, Proc. Natl. Acad. Sci., 97, 3455-3460, 2000).
  • Several in vitro and in vivo strategies have provided the proof of principal that inhibition of IGF-IR signaling reverses the transformed phenotype and inhibits tumour cell growth. These include neutralizing antibodies (Kalebic et al Cancer-Res., 54, 5531-5534, 1994), antisense oligonucleotides (Resnicoff et al, Cancer Res., 54, 2218-2222, 1994), triple-helix forming oligonucleotides (Rinninsland et al, Proc. Natl. Acad. Sci., 94, 5854-5859, 1997), antisense mRNA (Nakamura et al, Cancer Res., 60, 760-765, 2000) and dominant negative receptors (D'Ambrosio et al., Cancer Res., 56, 4013-4020, 1996). Antisense oligonucleotides have shown that inhibition of IGF-1R expression results in induction of apoptosis in cells in vivo (Resnicoff et al, Cancer Res., 55, 2463-2469, 1995) and have been taken into man (Resnicoff et al, Proc. Amer. Assoc. Cancer Res., 40 Abs 4816, 1999). However, none of these approaches is particularly attractive for the treatment of major solid tumour disease.
  • Since increased IGF signaling is implicated in the growth and survival of tumour cells, and bloking IGF-1R function can reverse this, inhibition of the IGF-1R tyrosine kinase domain is an appropriate therapy by which to treat cancer. In vitro and in vivo studies with the use of dominant-negative IGF-1R variants support this. In particular, a point mutation in the ATP binding site which blocks receptor tyrosine kinase activity has proved effective in preventing tumour cell growth (Kulik et al, Mol. Cell. Biol., 17, 1595-1606, 1997). Several pieces of evidence imply that normal cells are less susceptible to apoptosis caused by inhibition of IGF signaling, indicating that a therapeutic margin is possible with such treatment (Baserga, Trends Biotechnol., 14, 150-2,1996).
  • There are few reports of selective IGF-1R tyrosine kinase inhibitors. Parrizas et al. described tyrphostins that had some efficacy in vitro and in vivo (Parrizas et al., Endocrinology, 138:1427-33 (1997)). These compounds were of modest potency and selectivity over the insulin receptor. Telik Inc. have described heteroaryl-aryl ureas which have selectivity over insulin receptors but potency against tumour cells in vitro is still modest (Published PCT Patent Application No. WO 00/35455 ). WO 0164656 and WO 0039101 describe pyrimidine derivatives and their utility as anti-cancer agents.
  • In accordance with the present invention, there is provided a compound of formula (I):
    Figure imgb0001
     wherein
    R 1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino (-NH2), hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR5R6, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(O)mC1-C6alkyl, -C(O)NR7R8, -SO2NR7aR8a, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino (-NH2), hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR9R10, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(O)nC1-C6alkyl, -C(O)NR11R12 and -SO2NR11aR12a;
    m is 0, 1 or 2;
    n is 0, 1 or 2;
    R 2 represents a C1-C4alkyl group optionally substituted by at least one substituent selected from halogen, hydroxyl and C1-C3alkoxy;
    R 3 represents hydrogen, halogen or trifluoromethyl;
    R 4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino (-NH2), hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR13R14, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C4alkoxycarbonyl, C1-C4alkylcarbonyl, C1-C4alkylcarbonylamino, phenylcarbonyl, -S(O)pC1-C4alkyl, -C(O)NR15R16 and -SO2NR15aR16a;
    p is 0, 1 or 2;
    R 5 and R 6 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R7 and R8 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R7a and R8a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R7a and R8a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R9 and R10 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R11 and R12 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R11a and R12a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R11a and R12a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R13 and R14 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R15 and R16 each independently represent hydrogen, C1-C4alkyl or-C3-C6cycloalkyl, or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; and
    R15a and R16a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R15a and R16a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    or a pharmaceutically acceptable salt or solvate thereof.
  • In the context of the present specification, unless otherwise indicated, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. When R5 and R6, or R7 and R8, or R7a and R8a, or R9 and R10, or R11 and R12, or R11a and R12a, or R13 and R14, or R15 and R16, or R15a and R16a represent a saturated heterocycle, it should be understood that the only heteroatom present is the nitrogen atom to-which R5 and R6, or R7 and R8, or R7a and R8a, or R9 and R10, or R11 and R12 or R11a and 212a, or R13 and R14, or R15 and R16, or R15a and R16a are attached. In the definition of R1, it should be noted that the unsaturated 5- to 6-membered ring may have alicyclic or aromatic properties.
  • Examples of "C1-C6 alkyl" and "C1-C4alkyl" include methyl, ethyl, isopropyl and t-butyl. Examples of "C1-C6alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n-and t-butoxycarbonyl. Examples of "C1-C6alkoxy" and "C1-C3alkoxy" include methoxy, ethoxy and propoxy. Examples of "C1-C6alkylcarbonylamino" include formamido, acetamido and propionylamino. Examples of "S(O)mC1-C6alkyl" wherein m is 0 to 2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl Examples of "C1-C6alkylcarbonyl" include propionyl and acetyl. Examples of "C2-C6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C3-C6cycloalkyl" are cyclopropyl, cyclopentyl and cyclohexyl.
  • A "5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is a fully unsaturated, aromatic monocyclic ring containing 5 or 6 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which may, unless otherwise specified, be carbon or nitrogen linked. Suitably a "5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl; pyrrolyl or thienyl.
  • An "unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is a fully or partially unsaturated, monocyclic ring containing 5 or 6 atoms optionally of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, and which may, unless otherwise specified, be carbon or nitrogen linked. Suitably an "unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is phenyl or pyridyl.
  • A "5- membered heteroaromatic ring comprising art least one ring heteroatom selected from nitrogen, oxygen and sulphur" is a fully unsaturated, aromatic monocyclic ring containing 5 atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which may, unless otherwise specified, be carbon or nitrogen linked. Suitably a "5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur" is pyrazolyl.
  • R1 represents an optionally substituted 5- or 6-membered heteroaromatic ring comprising at least-one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of heteroaromatic rings include thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2-or 3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl), pyrazinyl (e.g. 2-pyrazinyl), pyridazinyl (e.g. 3-pyridazinyl), pyrimidinyl (e.g. 4- or 5-pyrimidinyl) and pyridyl (2-, 3- or 4-pyridyl).
  • In R1, the 5- or 6-membered heteroaromatic ring is optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from C1-C6, particularly C1-C4alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, - tert-butyl, n-pentyl or n-hexyl), C1-C6, particularly C1-C4alkoxy-(such as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, n-pentoxy or n-hexoxy) (each of the C1-C6alkyl and C1-C6alkoxy substituent groups being optionally substituted by at least one substituent, e.g. one, two, three or four substituents independently, selected from halogen (such as fluorine, chlorine bromine or iodine), amino, hydroxyl and trifluoromethyl), halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, -NR5R6, carboxyl, hydroxyl, C2-C6, particularly C2-C4alkenyl (such as ethenyl), C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C1-C6, particularly C1-C4alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C1-C6, particularly C1-Caalkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-C6, particularly C1-C4alkylcarbonylamino (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl, -S(O)mC1-C6, particularly C1-C4alkyl, -C(O)NR7R8, -SO2NR7aR8a, and an optionally substituted unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur.
  • Examples of the unsaturated 5- to 6-membered ring include phenyl, cylopentenyl, cyclohexenyl, thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2- or 3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl), pyrazinyl (e.g. 2-pyrazinyl), pyridazinyl (e.g. 3-pyridazinyl), pyrimidinyl (e.g. 4- or 5-pyrimidinyl) and pyridyl (2-, 3- or 4-pyridyl). The ring may itself be optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from C1-C6, particularly C1-C4alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-penty) or n-hexyl), C1-C6, particularly C1-C4alkoxy (such as methoxy, ethoxy, n-propoxy; n-butoxy, tert-butoxy, n-pentoxy or n-hexoxy) (each of the C1-C6alkyl and C1-C6alkoxy-substituent groups being optionally substituted by at least one substituent, e.g. one, two, three or four substituents independently, selected from halogen (such as fluorine, chlorine bromine or iodine), amino, hydroxyl and trifluoromethyl), halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, -NR9R10, carboxyl, hydroxyl, C2-C6, particularly C2-C4alkenyl (such as ethenyl), C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C1-C6, particularly C1-C4alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C1-C6, particularly C1-C4alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-C6, particularly C1-C4alkylcarbonylamino (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl -S(O)nC1-C6, particularly C1-C4alkyl, -C(O)NR11R12 and -SO2NR11aR12a.
  • Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
  • In one embodiment of the invention, R1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen, nitro, cyano, -NR5R6, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(O)mC1-C6alkyl, -C(O)NR7R8, -SO2NR7aR8a, and an unsaturated 6-membered ring which may comprise one ring nitrogen atom, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen, nitro, cyano, -NR9R10, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(O)nC1-C6alkyl, -C(O)NR11R12 and -SO2NR11aR12a.
  • In a further embodiment of the invention, R1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen, phenyl and pyridyl, each of the phenyl and pyridyl substituent groups itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy and halogen.
  • In an additional aspect R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen; oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from hydroxyl), halogen, -C(O)NR7R8, C1-C6alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen and oxygen, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen), halogen and cyano; wherein R7 and R8 are both hydrogen or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle.
  • In a further additional aspect R1 represents pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl or thienyl; said pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl and thienyl being optionally substituted by at least one substituent selected from methyl, isopropyl, hydroxymethyl, methoxy, chloro, bromo, carbamoyl, methoxycarbonyl, pyrrolidin-1-ylcarbonyl, phenyl and pyridyl; said phenyl or pyridyl being optionally substituted by at least one substituent selected from methyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, fluoro, chloro, bromo and cyano.
  • In a further additional aspect R1 represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid-5-yl, 2-cyanopyrid-5-yl, 3-bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-yl, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-yl, 6-methylpyrid-2-yl, 5,6-dimethylpyrid-2-yl, imidazol-4-yl, imidazol-5-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl, 3-methoxycarbonylisoxazol-5-yl, 3-(hydroxymethyl)isoxazol-5-yl, 3-carbamoylisoxazol-5-yl, 3-(pyrrolidin-1-ylcarbonyl)isoxazol-5-yl, 3-phenylisoxazol-5-yl, 3-(pyrid-2-yl)isoxazol-5-yl, 3-(2-methoxypyrid-3-yl)isoxazol-5-yl, 3-(2-methoxyphenyl)isoxazol-5-yl, 3-(3-methoxyphenyl)isoxazol-5-yl, 3-(2-ethoxyphenyl)isoxazol-5-yl, 3-(2-trifluoromethylphenyl)isoxazol-5-yl, 3-(2-trifluoromethoxyphenyl)isoxazol-5-yl, 3-(2-chlorophenyl)isoxazol-5-yl, 3-(2-bromophenyl)isoxazol-5-yl, 3-(2-methylphenyl)isoxazol-5-yl, 3-(2-fluorophenyl)isoxazol-5-yl, 3-(2-cyanophenyl)isoxazol-5-yl, 5-methylpyrazol-4-yl, fur-2-yl, fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl, 2-methylpyrazin-5-yl, pyridazin-3-yl, pyrimidin-4-yl, 1-methylpyrrol-2-yl and thien-3-yl.
  • R2 represents a C1-C4alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl and C1-C3alkoxy (e.g. methoxy, ethoxy and n-propoxy).
  • In one embodiment of the invention, R2 represents CH2 or (CH2)2.
  • In a further embodiment R2 represents a C1-C4alkyl group.
  • In an additional embodiment R2 represents methyl, ethyl and propyl.
  • R3 represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine) or trifluoromethyl.
  • In one embodiment of the invention, R3 represents chlorine or bromine.
  • In a further embodiment R3 represents hydrogen or halogen.
  • In an additional embodiment R3 represents hydrogen, chloro or bromo.
  • R4 represents an optionally substituted 5-membered heteroaromatic ring comprising at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of rings include thienyl (e.g. 3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2- or 3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl).
  • The 5-membered heteroaromatic ring in R4 is optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from C1-C6, particularly C1-C4alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C1-C6, particularly C1-C4alkoxy (such as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, n-pentoxy or n-hexoxy) (each of the C1-C6alkyl and C1-C6alkoxy-substituent groups being optionally substituted by at least one substituent, e.g. one, two, three or four substituents independently, selected from halogen (such as fluorine, chlorine bromine or iodine), amino, hydroxyl and trifluoromethyl), halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, -NR13R14, carboxyl, hydroxyl, C2-C6, particularly C2-C4alkenyl (such as ethenyl), C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C1-C4, particularly C1-C3alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C1-C4, particularly C1-C3alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl or n-butylcarbonyl), C1-C4, particularly C1-C3alkylcarbonylamino (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl, -S(O)pC1-C4, particularly C1-C2alkyl, -C(O)NR15R16 and -SO2NR15aR16a.
  • In one embodiment of the invention, R4 represents a 5-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen,-the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen, nitro, cyano, -NR13R14, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C4alkoxycarbonyl, C1-C4alkylcarbonyl, C1-C4alkylcarbonylamino, phenylearbonyl, -S(O)pC1-C4alkyl, -C(O)NR15R16 and -SO2NR15aR16a.
  • In a further embodiment of the invention, R4 represents a 5-membered heteroaromatic ring comprising two ring nitrogen atoms, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy, halogen and C3-C6cycloalkyl.
  • In an additional embodiment R4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl and C3-C6cycloalkyl.
  • In an additional further embodiment R4 represents pyrazolyl, the ring being optionally substituted by at least one substituent selected from methyl, ethyl, isopropyl, propyl, t-butyl and cyclopropyl.
  • In another further embodiment R4 represents 5-methylpyrazol-3-yl, 5-ethylpyrazol-3-yl, 5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl, 5-t-butylpyrazol-3-yl and 5-cyclopropylpyrazol-3-yl.
  • R5 and R6 each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R7 and R8 each independently represent hydrogen, C1-C-4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R7a and R8a each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R7a and R8a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R9 and R10 each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R11 and R12 each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl cyclopentyl and cyclohexyl), or R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R11a and R12a each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R11a and R12a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R13 and R14 each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R15 and R16 each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • R15a and R16a each independently represent hydrogen, C1-C4, particularly C1-C2alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), or R15a and R16a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).
  • In an embodiment of the invention, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, in which:
    • R1 represents a 5- or 6-membered heteroaromatic ring comprising one or two ring heteroatoms selected from nitrogen and oxygen, the ring being optionally substituted by at least one substituent selected from C1-C3alkyl, pyridyl, and phenyl optionally substituted by methoxy;
    • R2 represents a C1-C2alkyl group;
    • R3 represents chlorine or bromine; and
    • R4 represents pyrazolyl substituted by at least one substituent selected from C1-C4alkyl and cyclopropyl.
  • In a further aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:
    • R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from hydroxyl), halogen, -C(O)NR7R8, C1-C6alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen and oxygen, the ring itself being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen), halogen and cyano; wherein R7 and R8 are both hydrogen or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    • R2 represents a C1-C4alkyl group;
    • R3 represents hydrogen or halogen; and
    • R4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl and C3-C6cycloalkyl;
    or a pharmaceutically acceptable salt or solvate thereof.
  • In an additional aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:
    • R1 represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid-5-yl, 2-cyanopyrid-5-yl, 3-bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-yl, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-yl, 6-methylpyrid-2-yl, 5,6-dimethylpyrid-2-yl, imidazol-4-yl, imidazol-5-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl, 3-methoxycarbonylisoxazol-5-yl, 3-(hydroxymethyl)isoxazol-5-yl, 3-carbamoylisoxazol-5-yl, 3-(pyrrolidin-1-ylcarbonyl)isoxazol-5-yl, 3-phenylisoxazol-5-yl, 3-(pyrid-2-yl)isoxazol-5-yl, 3-(2-methoxypyrid-3-yl)isoxazol-5-yl, 3-(2-methoxyphenyl)isoxazol-5-yl, 3-(3-methoxyphenyl)isoxazol-5-yl, 3-(2-ethoxyphenyl)isoxazol-5-yl, 3-(2-trifluoromethylphenyl)isoxazol-5-yl, 3-(2-trifluoromethoxyphenyl)isoxazol-5-yl, 3-(2-chlorophenyl)isoxazol-5-yl, 3-(2-'bromophenyl)isoxazol-5-yl, 3-(2-methylphenyl)isoxazol-5-yl, 3-(2-fluorophenyl)isoxazol-5-yl, 3-(2-cyanophenyl)isoxazol-5-yl, 5-methylpyrazol-4-yl, fur-2-yl, fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl, 2-methylpyrazin-5-yl, pyridazin-3-yl, pyrimidin-4-yl, 1-methylpyrrol-2-yl and thien-3-yl;
    • R2 represents methyl, ethyl and propyl;
    • R3 represents hydrogen, chloro or bromo; and
    • R4 represents 5-methylpyrazol-3-yl, 5-ethylpyrazol-3-yl, 5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl,5-t-butylpyrazol-3-yl and 5-cyclopropylpyrazol-3-yl;
    or a pharmaceutically acceptable salt or solvate thereof.
  • Examples of compounds of the invention include:
    • 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-(3-isopropylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-(3-phenylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-[3-(2-methoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-[3-(2-methoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-meyhyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(2-fur-2-ylethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-(pyrid-3-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-(pyrid-2-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-[2-(imidazol-4-ylethyl)amino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(pyrid-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Chloro-2-[2-(pyrid-2-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-[2-(pyrid-3-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-yamino)pyrimidine,
    • 5-Bromo-2-(5-methylpyrazin-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    • 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine,
    and pharmaceutically acceptable salts and solvates of any one thereof.
  • In a further aspect of the invention, particular compounds of the invention are any one of Examples 3, 5, 8, 9, 11, 12, 34, 39, 40, 41, 47, 48, 68, 70 and 79 or pharmaceutically acceptable salts and solvates of any one thereof.
  • In another aspect of the invention, particular compounds of the invention are any one of the Examples or pharmaceutically acceptable salts and solvates of any one thereof.
  • The present invention further provides a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, which comprises:
    1. (i) reacting a compound of formula
      Figure imgb0002
       wherein L1 represents a leaving group (e.g. halogen or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy) and R3 and R4 are as defined in formula (I), with a compound of formula (III), H2N-R2-R1, wherein R1 and R2 are as defined in formula (I); or
    2. (ii) reacting a compound of formula
      Figure imgb0003
       wherein L2 represents a leaving group (e.g. halogen or sulphonyloxy such as methanesulphonyloxy or toluene-4-sulphonyloxy) and R1, R2 and R3 are as defined in formula (I), with a compound of formula (V), H2N-R4, wherein R4 is as defined in formula (I); or
    3. (iii) reacting a compound of formula
      Figure imgb0004
       wherein R1 and R2 are as defined in formula (I), with a compound of formula
      Figure imgb0005
       wherein X represents an oxygen atom and q is 1 or X represents a nitrogen atom and q is 2, each R20 independently represents a C1-C6alkyl group and R3 and R4 are as defined in formula (I); or
    4. (iv) when R4 represents a substituted pyrazolyl, reacting a compound of formula
      Figure imgb0006
    wherein R21 represents a C1-C6alkyl or C3-C6cycloalkyl group and R1, R2 and R3 are as defined in formula (I) with hydrazine;
    and optionally after (i), (ii), (iii) or (iv) carrying out one or more of the following:
    • converting the compound obtained to a further compound of the invention
    • forming a pharmaceutically acceptable salt or solvate of the compound.
  • Processes (i) and (ii) may conveniently be carried out as follows:
    1. a) in the presence of a suitable solvent for example a ketone such as acetone or an alcohol such as ethanol or butanol or an aromatic hydrocarbon such as toluene or N-methyl pyrrolid-2-one, optionally in the presence of a suitable acid for example an inorganic acid such as hydrochloric acid or sulphuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) and at a temperature in the range from 0°C to reflux, particularly reflux; or
    2. b) under standard Buchwald conditions (for example see J. Am. Chem. Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62, 1568 and 6066) for example in the presence of palladium acetate, in a suitable solvent for example an aromatic solvent such as toluene, benzene or xylene, with a suitable base for examples an inorganic base such as caesium carbonate or an organic base such as potassium-t-butoxide, in the presence of a suitable ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and at a temperature in the range from 25 to 80°C.
  • Process (iii) may conveniently be carried out in a suitable solvent such as N-methylpyrrolidinone or butanol at a temperature in the range from 100-200°C, in particular in the range from 150-170°C. The reaction is preferably conducted in the presence of a suitable base such as, for example, sodium methoxide or potassium carbonate.
  • Process (iv) may be carried out in a suitable solvent, for example, an alcohol such as methanol or butanol at a temperature in the range from 50-120°C, in particular in the range from 70-100°C.
  • Compounds of formulae (II), (III), (IV), (V), (VI), (VII) and (VIII) are either commercially available, are known in the literature or may be prepared using known techniques.
  • Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. Examples of the types of conversion reactions that may be used include introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid; the introduction of an acyl group using, for example, an acryl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of reduction reactions include the reduction of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating; and particular examples of oxidation reactions include oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at various stages, the addition and removal of one or more protecting groups.
  • The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).
  • The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. For example where R4 is pyrazolyl; pyraxolyl-5-yl and pyrazolyl-3-y] are tautomers of the same compound.
  • The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators or inhibitors of insulin-like growth factor-1 receptor (IGF-1R) activity, and may be used in the treatment of proliferative and hyperproliferative diseases/conditions, examples of which include the following cancers:
    1. (1) carcinoma, including that of the bladder, brain, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, thyroid and skin;
    2. (2) hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukaemia, B-cell lymphoma and Burketts lymphoma;
    3. (3) hematopoietic tumours of myeloid lineage, including acute and chronic myelogenous leukaemias and promyelocytic leukaemia;
    4. (4) tumours of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and
    5. (5) other tumours, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
  • The compounds of the invention are especially useful in the treatment of tumors of the breast and prostate.
  • Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy,
  • In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
  • The invention also provides a method of treating cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • The invention still further provides a method of modulating insulin-like growth factor-1 receptor (IGF-1R) activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is-in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene-oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example..sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30µ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
  • The size of the dose for therapeutic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • In general, a compound of the invention will be administered so that a daily dose in the range, for example, from 0.5 mg to 75 mg active ingredient per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, from 0.5 mg to 30 mg active ingredient per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, from 0.5 mg to 25 mg active ingredient per kg body weight will generally be used. Oral administration is however preferred. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active ingredient.
  • For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
    • Examples
  • The invention will now be further described with reference to the following illustrative examples in which, unless stated otherwise:
    • (i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
    • (ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 60°C;
    • (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica get plates;
    • (iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
    • (v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data;
    • (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
    • (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz, in DMSO-d6 +CD3COOD unless otherwise indicated;
    • (viii) chemical symbols have their usual meanings; SI units and symbols are used;
    • (ix) solvent ratios are given in volume:volume (v/v) terms; and
    • (x) mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (MH)+;
    • (xi) the following abbreviations have been used:
      THF
      tetrahydrofuran;
      DMF
      N,N-dimethylformamide;
      EtOAc
      ethyl acetate;
      DCM
      dichloromethane; and
      DMSO
      dimethylsulphoxide.
    Example 1 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino) pyrimidine.
  • A mixture of 5-aminomethyl,3-methylisoxazole hydrochloride (890mg, 6.0mmol), 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1; 578 mg, 2.0mmol) and N,N-diisopropylethylamine (1.4ml, 8.0mmol) in 1-butanol (10ml) was heated at 120°C for 18 hours. The mixture was allowed to cool to ambient temperature and volatiles removed by evaporation. The residue was triturated with ether and the product collected by filtration to give the titled compound (225mg, 31%). 1H NMR (DMSO): δ 2.15 (s, 3H), 2.2 (s, 3H), 4.5 (m, 2H), 6.1 (br s, 2H), 7.6 (br s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 366.
    • Examples 2 - 12
  • Following a similar procedure to Example 1, the following compounds were synthesised after replacement with a suitable pyrimidine (SM1) and amine (SM2) (the NMR was recorded in DMSO-d6). Where a starting material is not indicated, this compound is commercially available.
    Ex Compound NMR m/z SM1 SM2
    2 1 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.15 (s, 3H), 2.20 (s, 3H), 4.45 (d, 2H), 6.2-6.0 (m, 2H), 7.6 (br s, 1H), 7.95 (s, 1H), 8:5 (br s, 1H), 12.04 (br s, 1H) 320 Meth 10
    3 1,2 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-cyclopropyl-1 H-pyrazol-3-ylamino)pyrimidine 0.6 (br s, 2H), 0.9 (m, 2H), 1.8 (m, 1 H), 2.15 (s, 3H), 4.5 (m, 2H), 6.0-6.2 (br s, 2H), 8.05 (s, 1H) 390 Meth 11
    4 1 5-Chloro-2-(3-isopropylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 1.2 (d, 6H), 2.2 (s, 3H), 2.9 (m, 1H), 4.5 (m, 2H), 6.2 (br s, 2H), 7.6 (br s, 1H), 7.98 (s, 1H), 12.04 (br s, 1H) 348 Meth 10 Meth 57
    5 1,2 5-Chloro-2-(3-phenylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.2. (s, 3H), 4.6 (m, 2H), 6.78 (s, 1H), 7.4 (m, 3H), 7.6 (br s, 1H), 7.8 (m, 2H), 8.0 (s, 1H), 8.45 (s, 1H), 12.0 (br s, 1H) 382 Meth 10 Meth 56
    6 5-Bromo-2-[3-(2- 2.2 (s, 3H), 3.8 (s, 3H), 4.6 456 Meth Meth
    1,2 methoxyphenyl)isoxazol-5- ylmethylamino]-4-(5-methyl- 1H-pyrazol-3- ylamino)pyrimidine (m, 2H), 6.0-6.2 (m, 1H), 6.6 (s, 1H), 7.0 (t, 1H), 7.1 (d, 1H), 7.45 (m, 1H), 7.7 (s, 2H), 8.1. (s, 2H), 12.1 (br s, 1H) 1 58
    7 1,2 5-Chloro-2-[3-(2-methoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.2 (s, 3H), 3.8 (s, 3H), 4.5-4.7 (m, 2H), 6.0-6.4 (br s, 1H), 6.6 (s, 1H), 7.0 (t, 1H), 7.15 (d, 1H), 7.45 (m, 1H), 7.55-7.7 (m, 2H), 8.0 (s, 1H); 8.5 (br s, 1H), 12.05 (s, 1H) 412 Meth 10 Meth 58
    8 5-Chloro-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-1 H-pyrazol-3-ylamino)pyrimidine 2.2 (s, 3H), 4.6 (m, 2H), 6.7 (s, 1H), 7.43 (m, 1H), 7.63 (br s, 1 H), 7.9-8.0 (m, 3H), 8.48 (s, 1H), 8.65 (d, 1H), 12.02 (br 1H) 383 Meth 10 Meth 70
    9 1 5-Bromo-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.2 (s, 3H), 4.6 (m, 2H), 6.0-6.6 (m, 1H), 6.7 (s, 1H), 7.5 (m, 1H), 7.7 (br s, 1H), 7.9-8.2 (m, 4H), 8.7 (d, 1H), 12.1 (br s, 1H) 427 Meth 1 Meth 70
    10 1,2 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.25 (s, 9H), 2.05 (s, 3H), 4.50 (d, 2H), 6.05 (s, 1H), 7.60 (s, 1H), 8.05 (s, 1H), 12.07 (s, 1H) 406 Meth 12
    11 1,2 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine - 1.23 (s, 9H), 2.13 (s, 3H), 4.50 (d, 2H), 6.03 (br s, 1H), 6.32 (br s, 1H,), 7.55 (br s, 1H), 7.95 (s, 1H), 12.05 (br s, 1H) - 362 Meth 13
    12 2 5-Bromo-2-(3-methylisoxazol-5- 1.16 (t, 3H), 2.13 (s, 3H), 2.53 (q, 2H), 4.47 (d, 2H), 378 Meth 14
    ylmethylamino)-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine 6.05 (s, 1H), 7.58 (s, 1H), 8.03 (br s, 2H), 12.06 (s, 1H)
    1 Required aqueous work-up.
    2 Purified by column chromatography on silica gel eluting with DCM/methanol (95:5).
    • Example 13 5-Bromo-2-(2-fur-2-ylethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine
  • A mixture of 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method-1; 290mg, 10mmol), 2-(2-aminoethyl)furan (330mg, 3.0mmol) and 1-butanol (5ml) was heated at 120°C for 5 hours. The mixture was allowed to cool to ambient temperature and the volatiles removed by evaporation. The residue was dissolved in DCM and washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid product collected and purified by column chromatography on silica gel eluting with DCM /methanol (95:5) to give the titled compound (80mg, 22%). 1H NMR (DMSO): δ 2.1 (s, 3H), 2.85 (m, 2H), 3.45 (m 2H), 6.10 (m, 1H), 6.35 (m, 1H), 6.4 (br s, 1H), 7.15 (br s, 1H), 7.5 (s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 363.
    • Examples 14 - 106
  • Following a similar procedure to Example 13, the following compounds were synthesised after replacement with appropriate pyrimidine (SM1) and amine (SM2) starting materials. Where a starting material is not indicated, this compound is commercially available.
    Ex Compound NMR m/z SM1 SM2
    14 1,7 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.20 (s, 9H), 4.50 (d, 2H), 6.05 (s, 1H), 7.30 (m, 1H), 7.60 (m, 3H), 8.00 (s, 2H), 8.40 (d, 1H), 8.45 (s, 1H), 12.07 (s, 1H) 402 Meth 12
    15 2,7 5-Chloro-2-(pyrid-3-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.19 (s, 9H), 4.47 (d, 2H), 7.28 (t, 1H) 358 Meth 13
    16 2,7 5-Chloro-2-(pyrid-2-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.14 (s, 9H), 4.56 (d, 2H), 6.17 (br s, 1H), 7.61 (s, 1H), 7.69 (t, 1H), 7.94 (s, 1H), 8.39 (s, 1H), 8.46 (d, 1H), 12.01 (s, 1H) 358 Meth 13
    17 3,7 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.17 (s, 3H), 4.42 (d, 2H), 7.28 (m, 1H), 7.6 (m, 2H), 8.0 (br s, 2H), 8.4 (d, 1H), 8.5 (s, 1H), 12.01 (br s, 1H) 360 Meth 1
    18 3,7 5-Bromo-2-[2-(imidazol-4-ylethyl)amino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.2 (s, 3H), 2.75 (t, 2H), 3.45 (m, 2H), 6.4 (br s, 1H), 6.85 (s, 1H), 7.15 (br s, 1H), 7.5 (s, 1H), 8.0 (br s, 1H) 363 Meth 1
    19 4,5,7 5-Bromo-2-(pyrid-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.1 (br s, 3H), 4.5 (d, 2H), 7.2 (m, 2H), 7.6 (br s, 1H), 7.7 (m, 1H), 7.9 (s, 1H), 8.0 (s, 1H), 8.5 (d, 1H), 11.97 (br s, 1H) 360 Meth 1
    20 7 5-Chloro-2-[2-(pyrid-2-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.15 (s, 3H), 2.95 (m, 2H), 3.6 (m, 2H), 6.5 (s, 1H), 7.05 (br s, 1H), 7..2 (m, 2H), 7.65 (t, 1H), 7.9 (s, 1H), 8.3 (br s, 1H), 8.5 (m, 1H), 12.02 (br s, 1H) 330 Meth 10
    21 4,5,7 5-Bromo-2-[2-(pyrid-3-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.1 (br s, 3H), 2.9 (t, 2H), 3.5 (t, 2H), 6.4 (s, 1H), 6.95 (t, 1H), 7.05 (t, 1H), 7.1 (s, 1H), 7.3 (d, 1H), 7.5 (m, 1H), 8.0 (s, 1H) 374 Meth 1
    22 4,5,6,7 5-Bromo-2-(5-methylpyrazin-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.2 (s, 3H), 2.45 (s, 3H), 4.6 (d, 2H), 6.2 (s, 1H), 7.15 (br s, 1H), 8.0 (s, 1H); 8.4 (s, 1H), 8.43 (s, 1H) 375 Meth 1
    23 7 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5- 0.4-0.9 (m, 4H), 1.8 (br s, 1H), 4.4 (m, 2H), 5.8-6.5 (m, I H), 7.3 (m, 386 Meth 11
    cyclopropyl-1H-pyrazol- 3-ylamino)pyrimidine 1H), 7.6 (br s, 2H), 8.0 (s, 2H), 8.4 (m, 1H), 8.5 (s, 1H), 12.1-12.3 (m, 1H)
    24 5-Bromo-2-[3-(2-chlorophenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.19 (s, 3H), 4.64 (s, 2H), 5.74 (s, 1H), 6.18 (br s, 1H), 6.64 (s, 1H), 7.41-7.55 (m, 2H), 7.74 (t, 1H), 8.07 (s, 1H) 460 Meth 1 Meth 59
    25 5-Bromo-2-[3-(2-chlorophenyl)isoxazol-5-ylmethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.21 (s, 9H), 4.67 (s, 2H), 6.31 (br s, 1H), 6.60 (br s, 1H), 7.39-7.54 (m, 2H), 7.56-7.66 (m, 2H), 8.07 (s, 1H) 502 Meth 12 Meth 59
    26 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(pyrid-3-ylmethylamino) pyrimidine 2.12 (s, 3H), 4.46 (s, 2H), 6.05 (br s, 1H), 6.21 (br s, 1H), 7.26-7.35 (m, 2H), 7.70 (d, 1H), 7.79 (d, 1H), 8.39 (s, 1H), 8.55 (s, 1H) 282 Meth 15
    27 5-Bromo-2-[2-(3-methylisoxazol-5-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.18 (s, 6H), 2.96 (t, 2H), 3.51 (t, 2H), 6.12 (s, 1H), 6.36 (s, 1H), 8.02 (s, 1H) 378 Meth 1 Meth 83
    28 5-Chloro-2-[3-(2-chlorophenyl)isoxazol-5-ylmethylaminol-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyriinidine 1.21 (s, 9H), 4.65 (s, 2H), 6.31 (br s, 1H), 6.60 (br s, 1H), 7.39-7.52 (m, 2H), 7.57-7.65 (m, 2H), 7.99 (s, 1H) 458 Meth 13 Meth 59
    29 5-Chloro-4-(5-propyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine 0.88 (t, 3H), 1.50 (br s, 2H), 2.44 (br s, 2H), 4.53 (s, 2H), 5.87 (br s, 1H), 7.16-7.29 (m, 2H), 7.70 (t, H), 7.94 (s, 1H), 8.48 (d, 1H) 344 Meth 16
    30 5-Bromo-4-(5- 0.60 (br s, 2H), 0.89 (d, 2H), 1.78 386 Meth
    cyclopropyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine, (br s, 1H), 4.5 (s, 2H), 5.87 (br s, 1H), 7.16-7.31 (m, 2H), 7.69 (t, 1H), 8.01 (s, 1H), 8.49 (d, 1H) 11
    31 5-Chloro-4-(5-ethyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine 1.10 (br s, 3H), 2.44 (br s, 2H), 4.49 (s, 2H), 6.01 (br s, 1H), 7.17-7.29 (m, 2H), 7.70 (t, 1H), 7.93 (s, 1H), 8.49 (d, 1H) 330 Meth 17
    32 5-Bromo-4-(5-ethyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine 1.10 (br s, 3H), 2.54 (br s, 2H), 4.54 (s, 2H), 6.00 (br s, 1H), 7.17-7.30 (m, 2H), 7.69 (t, 1H), 7.99 (s, 1H), 8.49 (d, 1H) 374 Meth 14
    337 5-Bromo-4-(5-propyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine 0.88 (br s, 3H), 1.51 (br s, 2H), 2.45 (br s, 2H), 4.55 (s, 2H), 5.98 (br s, 1H), 7.15-7.30 (m, 2H), 7.59 (s, 1H), 7.72 (t, 1H), 7.95 (s, 1H), 8.01 (s, 1H), 8.50 (d, 1H), 11.98 (s, 1H) 388 Meth 18
    347 5-Chloro-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.19 (s, 3H), 4.61 (s, 2H), 6.21 (br s, 1H), 6.66 (s, 1H), 7.27-7.40 (m, 2H), 7.50-7.60 (m, 1H), 7.66 (br s, 1H), 7.86 (t, 1H), 7.99 (s, 1H), 8.50 (br s, 1H), 12.04 (s, 1H) 400 Meth 10 Meth 60
    35 5-Chloro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine 1.15 (br s, 6H), 2.81 (br s, 1H), 4.55 (s, 2H), 6.20 (br s, 1H), 7.15-7.32 (m, 2H), 7.71 (t, I H), 7.95 (s, 1H), 8.46 (d, 1H) 344 Meth 19
    36 7 5-Bromo-4-(5-tert-butyl-1H-pyrazol-3-ylamino)-2-[3-(2-trifluoromethoxyphenyl) isoxazol-5- 1.26 (s, 9H), 4.65 (s, 2H), 6.28 (br s, 1H), 6.56 (br s, 1H), 7.46-7.56 (m, 2H), 7.62-7.66 (m, 1H), 7.72 (br s, 1H), 7.85 (d, 1H), 8.05 (s, 1H), 12.06 (s, 1H) 552 Meth 12 Meth 61
    ylmethylamino] pyrimidine
    37 5-Chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine 0.60 (br s, 2H), 0.88 (d, 2H), 1.78 (br s, 1H), 4.52 (s, 2H), 5.95 (br s, 1H), 7.16-7.31 (m, 2H), 7.69 (t, 1H), 7.91 (s, 1H), 8.50 (d, 1H) 342 Meth 20
    388 5-Chloro-2-[3-(2-cyanophenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.18 (s, 3H), 4.68 (s, 2H), 6.27 (s, 1H), 6.77 (s,1H), 7.64 (dt, 1H), 7.77 (dt, 1H), 7.84 (dd, 1H), 7.90 (dd, 1H), 7.96 (s, 1H) 407 Meth 10 Meth 81
    39 5-Bromo-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.19 (s, 3H), 4.63 (s, 2H), 6.27 (br s, 1H), 6.66(s, 1H), 7.30-7.44 (m, 2H), 7.50-7.61 (m, 1H), 7.87 (t, 1H), 8.09 (s, 1H) 444 Meth 1 Meth 60
    407 5-Chloro-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.22 (s, 9H), 4.67 (s, 2H), 6.38 (br s, 1H), 6.64 (br s, 1H), 7.28-7.41 (m, 2H), 7.50-7.59 (m, 1H), 7.69 (br s, I H), 7.85 (t, 1H), 8.00 (s, 1H), 8.54 (br s, 1H), 12.10 (s, I H) 442 Meth 13 Meth 60
    41 5-Bromo-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-yl methylamino) pyrimidine 1.01 - 1.25 (m, 6H), 2.84 (br s, 1H), 4.56 (s, 2H), 6.12 (br s, 1H), 7.19-7.34 (m, 2H), 7.72 (t, 1H), 8.04 (s, 1H), 8.49 (d, 1H) 388 Meth 21
    42 7 5-Bromo-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylaminol-4-(5-tert-butyl-1H-pyrazol-3- ylamino)pyrimidine 1.22 (s, 9H), 4.66 (s, 2H), 6.34 (br s, 1H), 6.62 (br s, 1H), 7.28-7.43 (m, 2H), 7.51-7.61 (m, 1H), 7.72 (br s, 1H), 7.86 (t, 1H), 8.01-8.18 (br s, 2H), 12.10 (s, 1H) 486 Meth 12 Meth 60
    438 5-Bromo-2-[3-(2- 1.69 (s, 3H), 4.20 (s, 2H), 5.78 (s, 451 Meth Meth
    cyanophenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 1 H), 6.27 (s, 1H), 7.15 (dt, 1H), 7.28 (dt, 1H), 7.35 (dd, 1H) 7.41 - (dd,1H), 7.55(s, 1H) 1 81
    44 9 5-Bromo-2-[1-(3-methylisoxazol-5-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 1.50 (s, 3H), 2.18 (s, 3H), 2.22 (s, 3H), 5.18 (q, H), 6.10 (s, H), 6.23 (br s, H), 7.68 (br s, H), 8.09 (s, H), 8.53 (br s, H) 378 Meth 1 Meth 72
    45 9 5-Chkror-2-[1-(3-methylisoxazol-5-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 1.50 (s, 3H), 2.15 (s, 3H), 2.24 (s, 3H), 5.18 (q, H), 6.10 (s, H), 6.21 (br s, H), 7.73 (br s, H), 8.01 (s, H), 8.99 (br s, H) 334 Meth 10 Meth 72
    46 7 5-Bromo-4-(5-ethyl-1H-pyrazol-3-ylamino)-2-(pyrid-3-ylmethylamino) pyrimidine 1.10 (t, 3H), 2.54 (q, 2H), 4.42 (d, 2H), 7.26 (t, 1H), 7.50-7.68 (m, 2H), 7.92-8.05 (m, 2H), 8.37 (d, 1H), 8.45 (s, 1H), 12.04 (br s, 1H) 374 Meth 14
    47 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-propyl-1H-pyrazol-3-ylamino)pyrimidine 0.85 (t, 3H), 1.58 (m, 2H), 2.10 (s, 3H), 2.50 (t, 2H), 4.50 (s, 2H), 6.05 (s, 1H), 8.00 (s, 1H) 392 Meth 18
    48 5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-isopropyl-1H-pyrazol-3-ylamino)pyrimidine 1.18 (d, 6H), 2.10 (s, 3H), 2.85 (m, 1H), 4.5 (s, 2H), 6.00 (s, 1H), 6.30 (br s, 1H), 8.00 (s, 1H) 392 Meth 21
    49 5-Bromo-2-[3-(2-ethoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.25 (br s, 12H), 4.04 (q, 2H), 4.62 (s, 2H), 6.35 (br s, 1H), 6.65 (s, 1H), 7.00 (t, 1H), 7.10 (d,1H), 7.40 (t, 1H), 7.70 (d, 1H), 8.07 (s, 1H) 512 Meth 12 Meth 62
    50 5-Bromo-4 -(5-tert-butyl-1H-pyrazol-3-ylamino)-2-[3-(2-trifluoromethylphenyl) isoxazol-5-ylmethylamino] pyrimidine 1.30 (s, 9H), 4.75 (s, 2H), 6.35 (bur s, 1H) 6.43, (br s, 1H), 7.58 (d, 1H), 7.75 (m, 2H), 7.87 (d, 1H), 8.20 (s, 1H) 536 Meth 12 Meth 63
    51 5-Bromo-2-[3-(2- methylphenyl)isoxazol- 2H), 6.36 (br s, 1H), 6.54 (br s, 5-y)methylamino]-4-(5- 1H), 7.32 (m, 3H), 7.44 (d, 1H), tert-butyl-1H-pyrazol-3- 8.20 (s, 1H) ylamino)pyrimidine 1.23 (s, 9H), 2.36 (s, 3H), 4.65 (s, 482 Meth 12 Meth 64
    527 5-Bromo-2-[2-(pyridazin-3-yl)ethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.19 (br s, 9H), 3.19 (t, 2H), 3.65 (q, 2H), 6.41 (br s, 1H), 7.54 (m, 2H), 7.98 (s, 1H), 9.06 (d, 1H) 417 Meth 12 J Am Chem Soc, 1950, 72, 3539
    53 5-Bromo-2-[3-(2-bromophenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine -2.18 (s, 3H), 4.63 (s, 2H), 6.3 (bd, 1H), 6.62 (br s, 1H), 7.49 (m,3H), 7.76 (d, 1H), 8.07 (s, 1H) 506 Meth 1 Meth 65
    54 5-Bromo-2-[2-(pyrimidin-4-yl)ethytamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.19 (s, 9H), 2.98 (t, 2H), 3.62 (q, 2H), 6.36 (s, 1H), 7.37 (d, 1H), 8.13 (s, 1H), 8.62 (d, 1H), 9.04 (s, 1 H) 417 Meth 12 J Am Chem Soc, 1950, 72, 3539
    55 7 5-Bromo-2-(pyrazin-2-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.19 (s, 9H), 4.57 (d, 2H), 6.16 (br s, 1H), 8.01 (s, 1H), 8.48 (s, 1H), 8.52 (s, 2H) 403 Meth 12
    56 5-Bromo-2-(5-methylisoxazol-3-ylmethylamino)-4-(5- . tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.24 (s, 9H), 2.38 (s, 3H), 4.43 (s, 2H), 6.07 (s, 1H), 6.41 (s, 1H), 8.04 (s, 1H) 406 Meth 12 Meth 85
    57 7 5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-propyl-1H-pyrazol-3-ylamino)pyrimidine 0.86 (t, 3H), 1.52 (m, 2H), 2.47 (m, 2H), 4.45 (d, 2H), 6.04 (br s, 1H), 7.29 (t; I H), 7.60 (bt, 1H), 8.00 (s, 1H), 8.39 (d, 1H), 8.48 (s, 1H) 388 Meth 18
    58 5-Bromo-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-(pyrid-3-ylmethylamino) pyrimidine 1.14 (s, 6H), 2.84 (m, 1H), 4.46 (s, 2H), 6.18 (br s, 1H), 7.28 (t, 1H), 7.63 (bt, 1H), 8.00 (s, 1H), 8.38 (d, 1H), 8.47 (s, 1H) 388 Meth 21
    59 5-Bromo-2-[3-(2-methoxypyrid-3-yl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.19 (s, 3H), 3.93 (s, 3H), 4.62 (s, 2H), 6.30 (br s, 1H), 6.70 (s, 1H), 7.12 (dd, 1H), 8.07 (s, 1H), 8.14 (dd, 1H), 8.29 (dd, 1H) 457 Meth 1 Meth 66
    607 5-Bromo-2-[3-(3-methylpyrazol-4-yl)propylamino]-4-(5- tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.25 (s, 9H), 1.71 (m,2H), 2.06 (s, 3H), 2.34 (m, 2H), 3.24 (m, 2H), 6.47 (br s, 1H), 7.05 (br s, 1H), 7.30 (br s, 1H), 7.97 (s, 1H), 12.06 (br s, 1H) 433 Meth 12
    617 - 5-Bromo-2-[3-(3-methylpyrazol-4-yl)propylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 1.70 (m, 2H), 2.08 (s, 3H), 2.18 (s, 3H), 2.36 (t, 2H), 3.20 (m, 2H), 6.40 (br s, 1H), 7.03 (br s, 1H), 7.26 (s, 1H), 7.97 (s, 2H), 12.04 (s, 1H) 391 Meth 1
    62 5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)- 2.12 (s, 3H), 4.5 (d, 2H), 7.07-7.36 (m, 2H), 7.51 (br s, 1H), 7.67 316 Meth 10
    2-(pyrid-2-ylmethylamino) pyrimidine (m, 1H), 7.91 (s, 1H), 8.34 (s, 1H), 8.48 (d, 1H), 11.96 (br s, 1H)
    63 5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2-(pyrid-3-ylmethylamino) pyrimidine 2.15 (s, 3H), 4.43 (m, 2H), 7.29 (s, 1H),-7.43-7.74 (m, 2H), 7.92 (br s, 1H), 8.23-8.56 (m, 3H), 12.0 (br s, 1H) 316 Meth 10
    64 5-Bromo-4-(5-methyl-1H-pyrazol-3-ylamino)-2-(pyrid-4-ylmethylamino) pyrimidine 2.13 (s, 3H), 4.43 (d, 2H), 7.24 (d, 2H), 7.63 (br s, 1H), 7.99 (s, 2H), 8.44 (d, 2H), 11.99 (br s, 1H) 360 Meth
    65 5-Chloro-2-[2-(imidazol-5-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.15 (s, 3H), 2.74 (m, 2H), 3.43 (m, 2H), 6.48 (br s, 1H), 6.77 (br s, 1H), 7.01 (br s, 1H), 7.5 (s, 1H), 7.9 (br s, 1H), 8.31 (br s, 1H), 11.6-12.1 (m, 2H) 319 Meth 10
    66 5-Chloro-2-[3-(3-methoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.19 (s, 3H), 3.81 (s, 3H), 4.61 (s, 2H), 6.05-6.45 (m, 1H), 6.81 (s, 1 H), 7.03 (m, 1H), 7.36-7.40 (m, 4H), 7.99. (s, 1H) 412 Meth 10 Meth 67
    67 5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2- 2-[3-(pyrid-3-yl)isoxazol-5-ylmethylamino] pyrimidine 2.16 (s, 3H), 4.60 (s, 2H), 5.97-6.43 (m, 1H), 6.88 (br s, 1H), 7.49 (m, 1H), 7.96 (s, 1H), 8.20 (m, 1H), 8.64 (m, 1H), 9.0 (br s, 1H) 383 Meth 10 Meth 68
    68 5-Chloro-2-[3-(pyrid-2-yl)isoxazol-5-ylmethylamino]-4-(5-tert-butyl-1H-pyrazol-3- 1.24 (s, 9H), 4.66 (s, 2H), 6.34 (br s, 1H), 6.73 (br s, 1H), 7.48 (t, 1H), 7.89-7.99 (m, 3H), 8.65 (d, 1H) 425 Meth 13 Meth 70
    ylamino)pyrimidine
    69 5-Bromo-4-(5-propyl-1H-pyrazol-3-ylamino)2-[3-(pyrid-2-yl)isoxazol-5-ylmethylamino] pyrimidine 0.85 (brs, 3H), 1.55 (br s, 2H), 2.5 (2H, m), 4.63 (s, 2H), 6.05-6.52 (m, 1 H), 6.74 (br s, 1H), 7.47 (t, 1H), 7.88-7.99 (m, 2H), 8.07 (s, 1H), 8.66 (d, 1H) 455 Meth 18 Meth 70
    70 5-Bromo-2-[3-(pyrid-2-yl)isoxazol-5-ylmethylaminol-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.23 (s, 9H), 4.66 (s, 2H), 6.34 (br s, 1H), 6.73 (br s, 1H), 7.48 (m , 1H), 7.86-8.02 (m, 2H), 8.08 (s, 1H), 8.65 (d, 1H) 469 Meth 12 Meth 70
    71 5-Bromo-4-(5-ethyl-1H-pyrazol-3-ylamino)-2-[3-(pyrid-2-yl)isoxazol-5-ylmethylamino] pyrimidine 1.15 (m, 3H), 2.54 (m, 2H), 4.64 (s, 2H), 6.05-6.53 (br s, 1 H), 6.74 (br s, 1H), 7.46 (m, 1H), 7.84-8.02 (m, 2H), 8.07 (s, 1H), 8.65 (d, 1H) 441 Meth 14 Meth 70
    72 5-Bromo-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-[3-(pyrid-2-yl)isoxazol-5-ylmethylamino] pyrimidine 1.17 (m, 6H), 2.80-2.95 (m, 1 H), 4.64 (br s, 1H), 6.18-6.48 (br s, 1H), 6.73 (br s; 1H), 7.46 (m, 1H), 7.82-8.00 (m, 2H), 8.07 (s, 1 H), 8.64 (d, 1H) 455 Meth 21 Meth 70
    73 10 5-Bromo-2-(5-methylfur-2-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.24 (s, 9H), 2.21 (s, 3H), 4.48 (s, 2H), 5.97 (s, 1H), 6.06 (br s, 1H); 6.40 (br s, 1H), 8.32 (s, 1 H) 405 Meth 12
    74 10 5-Bromo-2-(fur-3-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.25 (s, 3H), 4.37 (s, 2H), 6.24 (s, 1H); 6.47 (s, 1H), 7.52 (s, 1H), 7.61 (s, 1H), 8.35 (s, 1H) 349 Meth 1
    75 10 5-Bromo-2-(2-cyanopyrid-5- 1.15 (s, 9H), 4.62 (s, 2H), 6.05 (s, 1H), 7.86 (m, 1H), 7.93 (d, 1H), 427 Meth 12 WO 02 /
    ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 8.38 (s, 1H), 8.60 (s, 1H) 44145
    76 10 5-Bromo-2-(pyrad-2-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.19 (s, 9H), 4.87 (s, 2H), 6.04 (s, 1H), 7.90 (m, 2H), 8.46 (m, 2H), 8.83 (d, 1 H) 402 Meth 12
    77 10 5-Bromo-2-(fur-3-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.24 (s, 9H), 4.40 (s, 2H), 6.36 (br s, 1H), 6.43 (br s, 1H), 7.48 (br s, 1H), 7.57 (br s, 1H), 8.35 (s, 1H) 391 Meth 12
    78 10 5-Bromo-2-(2-methoxypyrid-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.21 (s, 9H), 3.92 (s, 3H), 4.72 (s, 2H), 6.16 (s, 1H), 7.61 (m, 1H), 7.83 (d, 1H), 8.45 (m, 2H) 432 Meth 12 WO 95/ 18097
    79 10 5-Bromo-2-(3-bromopyrid-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.17 (s, 9H), 4.60 (s, 2H), 6.13 (s, 1H), 8.10 (s, 1H), 8.38 (s, 1H), 8.52 (s, 1H), 8.70 (s, 1H) 480 Meth 12 WO 99 / 00385
    80 10 5-Bromo-2-(fur-2-ylmethylamino)-4-(5-tert-butyl-1 H-pyrazol-3-ylamino)pyrimidine 1.24 (s, 9H), 4.56 (s, 2H), 6.21 (s, 1H), 6.39 (br s, 2H), 7.59 (s, 1H), 8.34 (s, 1 H) 391 Meth 12
    81 10 5-Bromo-4-(5-methyl-1H-pyrazol-3-ylamino)-2-[2-(thien-3-yl)ethylamino] pyrimidine 2.21 (s, 3H), 2.88 (m, 2H), 3.57 (m, 2H), 6.34 (s, 1 H), 6.97 (br s, 1H), 7.20 (br s, 1H), 7.49 (m, 1H), 8.33 (s, 1H) 379 Meth 1
    827 5-Bromo-2-[2-(1-methylpyrrol-2-yl)ethylamino]-4-(5- 2.10 (m, 3H), 2.75 (t, 2H), 3.3-3.4 (m, 5H), 5.80 (s, 1H), 5.87 (s, 1H), 6.37 (m, 1H), 6.60 (s, 1H), 376 Meth 1 Tetrah edron 1999,
    methyl-1H-pyrazol-3-ylamino)pyrimidine 7.16 (m, 1H), 8.03 (m, 2H) 55, 11619 - 11640
    83 5-promo-2-(3-phenylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.15 (s, 3H), 4.6 (s, 2H), 6.0-6.5 (br s, 1H), 6.75 (br s, 1H), 7.44 (m, 3H), 7.8 (m, 2H), 8.05 (s, 1H) 426 Meth 1 Meth 56
    84 5-Bromo-2-[4-(pyrid-2-yl)pyrid-2- ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.11 (s, 3H), 4.61 (s, 2H), 6.1 (br s, 1H), 7.42 (t, 1H), 7.98 (m, 4H), 8.00 (s, 1H), 8.60 (d, 1H), 8.67 (d, 1H) 437 Meth 1 Meth 100
    85 5-Bromo-2-[5-(pyrid-2-yl)pyrid-3-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.12.(s, 3H), 4.54 (s, 2H), 6.20 (br s, 1H), 7.39 (t, 1 H), 7.89 (m, 2H), 8.02 (s, 1 H), 8.37 (s, 1H), 8.55 (s, 1H), 8.69 (d, 1H), 9.08 (s, 1H) 437 Meth 1 Meth 102
    86 5-Chloro-2-[5-(pyrid-2-yl)pyrid-3-ylmethylamino]-4-(5-methyl-1H-pyrazol-3- ylamino)pyrimidine 2.12 (s, 3H), 4.54 (s, 2H), 6.20 (br s, 1H), 7.89 (m, 2H), 7.94 (s, 1H), 8.38 (s, 1H), 8.56 (s, 1H), 8.67 (d, 1H), 9.08 (s, 1H) 393 Meth 10 Meth 102
    87 5-Bromo-2-(6-chloropyrid-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3- ylamino)pyrimidine 2.15 (s, 3H), 4.48 (s, 2H), 5.85 (br s, 1H), 7.25 (d, 1H), 7.35 (d, 1H), 7.75 (t, 1H), 8.00 (s, 1H) 394 Meth 1 Meth 94
    88 5-Bromo-2-(3-methylpyrid-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3- 2.17 (s, 3H), 2.30 (s, 3H), 4.55 (s, 2H), 6.20 (br s, 1H), 7.20 (t, 1H), 7.55 (d, 1H), 8.03 (s, 1H), 8.35 (d, 1H) 374 Meth 1 Meth 97
    ylamino)pyrimidine
    89 5-Bromo-2-(6-methylpyrid-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3- ylamino)pyrimidine 2.12 (s, 3H), 2.45 (s, 3H), 4.48 (s, 1H), 6.00 (br s, 1H), 7.08 (d, 2H), 7.55 (t, 1H), 8.00 (s, 1H) 374 Meth 1 Meth 95
    90 5-Bromo-2-(5,6-dimethylpyrid-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.10 (s, 3H), 2.18 (s, 3H), 2.40 (s, 3H), 4.45 (s, 2H), 6.10 (br s, 1H), 7.03 (d, 1H), 7.45 (d, 1H), 7.98 (s, 1H) 388 Meth 1 Meth 96
    91 5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-isopropyl-1H-pyrazol-3-ylamino)pyrimidine 1.20 (d, 6H), 2.15 (s, 3H), 2.88 (m, 1H), 4.50 (s, 2H), 6.08 (s, 1H), 6.30 (s, 1H), 7.95 (s, 1H) 348 Meth 19
    92 5-Bromo 4-(5-methyl-1H-pyrazol-3-ylamino)-2-[1-(pyrid-2-yl)ethylamino] pyrimidine 1.45 (d, 3H), 2.15 (s, 3H), 5.00 (s, 1H), 5.95 (br s, 1H), 7.18 (m, 1H), 7.35 (d, 1H), 7.68 (t, 1H), 7.95 (s, 1H), 8.50 (d, 1H) 374 Meth 1 Meth 91
    93 5-Bromo-4-(5-methyl-1H-pyrazol-3-ylamino)-2-[1-(pyrid-3-yl)ethylamino] pyrimidine 1.45 (d, 3H), 2.17 (s, 3H), 4.98 (s, 1H), 6.00 (br s, 1H), 7.30 (m, 1H), 7.75 (d, 1H), 7.93 (s, 1H), 8.38 (d, 1 H), 8.55 (s, 1 H) 374 Meth 1 Meth 90
    94 5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2-[1-(pyrid-3-yl)ethylamino] pyrimidine 1.45 (d, 3H), 2.18 (s, 3H), 5.00 (s, 1H), 6.00 (brs, 1H), 7.33 (m, 1H), 7.75 (d, 1H), 7.90 (s, 1H), 8.38 (m, 1 H), 8.56 (s, 1 H) 330 Meth 10 Meth 90
    95 5-Bromo-4-(5-methyl-1H-pyrazol-3-ylamino)- 0.88 (t, 3H), 1.85 (m, 2H), 2.18 (s, 3H), 4.80 (s, 1H), 6.00 (br s, 1H), 388 Meth 1 Meth 92
    2-[1-(pyrid-2-yl)propylamino] pyrimidine 7.20 (m, 1H), 7.33 (d, 1H), 7.69 (t; 1H), 7.95 (s, 1 H), 8.45 (d, 1H)
    96 5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2-[1-(pyrid-2-yl)propylamino] pyrimidine 0.87 (t, 3H), 1.80 (m, 2H), 2.19 (s, 3H), 4.83 (s, 1H), 6.00 (br s, 1H), 7.18 (m, 1 H), 7.33 (d, 1H), 7.67 (t, 1H), 7.87 (s, 1H), 8.47 (d, 1H) 344 Meth 10 Meth 92
    97 5-Bromo-4-(5-methyl1H-pyrazol-3-ylamino)2-[1-(pyrid-3-yl)propylamino] pyrimidine 0.85 (t, 3H), 1.73 (m, 2H), 2.15 (s, 3H), 4.73 (s, 1 H), 6.00 (br s, 1 H), 7.30 (m, 1H), 7.70 (d, 1H), 7.93 (s, 1H), 8.35 (d, 1H), 8.50 (s, 1H) 388 Meth 1 Meth 93
    98 5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2-[1-(pyrid-3-yl)propylamino] -pyrimidine 0.89 (t, 3H), 1.77 (m, 2H), 2.20 (s, 3H), 4.78 (s, 1H), 6.05 (br s, 1H), 7.30 (t, 1H), 7.75 (d, 1H), 7.85 (s, 1H), 8.38 (d, 1H), 8.52 (s, 1H) 344 Meth 10 Meth 93
    99 5-Bromo-2-(3- bromopyrid-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 1.19 (s, 3H), 4.43 (d, 2H), 6.02 (br s, 1H), 7.65 (t, 1H), 7.90 (s, 1H), 8.04 (s, 1H), 8.46 (s, 1H), 8.55 (s, 1H), 12.10 (br s, 1H) 440 Meth 1 WO 99/ 00385
    100 11 5-Bromo-2-[2-(1-methylpyrrol-2-yl)ethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 1.48 (s, 9H), 3.07 (t, 2H), 3.71 (s, 3H), 3.80 (m, 2H), 6.07 (s, 1H), 6.13 (t, 1H), 6.74 (m, 2H), 8.17 (s, 1H) 418 Meth 12 Tetrah edron 1999 (55), 11619 - 11640
    101 5-Bromo-2-[2-(pyrimidin-5-yl)ethylamino]-4-(5-tert- 1.26 (s, 9H), 2.92 (m, 2H), 3.62 (t, 2H), 6.38 (s, 1H), 8.35 (s, 1H), 8.73 (s, 2H), 9.14 (s, 1H) 417 Meth 12 J Am Chem Soc,
    butyl-1H-pyrazol-3-ylamino)pyrimidine 1950, 72, 3539 12
    102 5-Chloro-2-(pyrid-3- ylmethylamino)-4-(5-propyl-1H-pyrazol-3-ylamino)pyrimidine 0.84 (t, 3H), 1.50 (m, 2H), 2.45 (m, 2H), 4.46 (s, 2H), 6.18 (br s, 1H), 7.30 (t, 1H), 7.67 (d, I H), 7.91 (s, 1H), 8.38 (d, 1H), 8.48 (s, 1H) 344 Meth 16
    103 5-Chloro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-(pyrid-3-ylmethylamino) pyrimidine 1.13 (d, 6H), 2.84 (m, 1H), 4.47 (s, 2H), 6.24 (br s, 1H), 7.29 (t, 1H), 7.65 (d, 1H), 7.92 (s, 1H), 8.39 (d, 1H), 8.49 (s, 1H) 344 Meth 19
    104 5-Bromo-2-[3-(methoxycarbonyl)isoxaz ol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.17 (s, 3H), 3.84 (s, 3H), 4.59 (s, 2H), 6.21 (br s, 1H), 6.58 (s, 1H), 8.03 (s, 1H) 408, Meth 1 Meth 74 13
    105 5-Bromo-2-[3-(pyrrolidin-1-ylcarbonyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 1.86 (m, 4H), 2.18 (s, 3H), 3.44 (t, 2H), 3.57 (t, 2H), 4.58 (s, 2H), 6.20 (br s, 1H), 6.44 (s, 1H), 8.04 (s, 1H) 447 Meth 1 Meth 78
    106 5-Bromo-2-[3-(hydroxymethyl)isoxazol -5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine 2.17 (s, 3H), 4.40 (s, 2H), 4.50 (s, 2H), 6.17 (s, 1 H), 6.28 (br s, 1H), 8.02 (s, 1H) 380 Meth 1 Meth 76
    1 Heated for 12 hours.
    2 Heated for 24 hours.
    3 Reaction treated with 2M NH3/MeOH to pH 9. Precipitate was filtered and washed with distilled water and diethyl ether.
    4 No aqueous work-up, product precipitates from DCM.
    5 No chromatography necessary.
    6 500MHz (393K).
    7 NMR run with no d4 acetic acid.
    8 NMR run at 373K/400MHz.
    9 NMR run with no d4 acetic acid at 343K.
    10 NMR: Trifluorodeuterated acetic acid-d1 use in place of acetic aicd-d4.
    11 NMR run in CD3OD.
    12 Compound could be prepared by the procedure described in this paper.
    13 Ester exchange with the methanol used in the chromatography occurred.
    • Example 107 5-Bromo-2-(3-carbamoylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine
  • 5-Bromo-2-[3-(methoxycarbonyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 104; 50mg, 0.11 mmol) was suspended in 7N methanolic ammonia (5ml) and stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was triturated with DCM/diethyl ether (50:50) and the product collected by filtration to give the title compound (35mg, 76%). NMR (DMSO): 2.18 (s, 3H), 4.57 (d, 2H), 6.28 (br s, 1H), 6.50 (s, 1H), 7.72 (s, 2H), 8.01 (s, 1H), 8.05 (s, 1H), 12.06 (s, 1H); m/z 393 (MH)+.
    • Preparation of Starting Materials :-
  • The starting materials for the examples above are either commercially available or are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials used in the above reactions.
    • Method 1 5-Bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine
  • A solution of 5-bromo-2,4-dichloropyrimidine (10.0g, 44mmol), 3-amino-5-methyl-1H-pyrazole (6.0g, 62mmol) and N,N-diisopropylethylamine (9.29ml, 53mmol) in 1-butanol (80ml) was heated at 85°C for 12 hours. The mixture was allowed to cool to ambient temperature and the resulting precipitate collected by filtration. The solid product was washed with ethanol and dried to give the sub-titled compounds (10.8g, 85%). 1H NMR (DMSO): δ 2.23 (s, 3H), 6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); MS: m/z 290 (MH)+.
    • Method 2 2-Oxobutylnitrile
  • Acetonitrile (13.7ml, 260mmol) was added to a suspension of sodium hydride (10.4g of a 60% suspension in mineral oil, 260mmol) in ethyl propionate (22.3g, 220mmol) and anhydrous 1,4-dioxane (200ml) at ambient temperature. The mixture was heated at 100°C for 12 hours and then allowed to cool. Water was added, the mixture adjusted to pH 2.0 with concentrated hydrochloric acid and extracted with DCM. The extracts were combined dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with DCM to give the title compound (20g, 94%) as an oil. NMR (CDCl3): 1.10 (t, 3H), 2.65 (q, 2H), 3.50 (s, 2H).
    • Methods 3 - 5
  • The following compounds were prepared by the procedure of Method 2 using the appropriate starting materials.
    Method Compound
    3 2-Cyclopropyl-2-oxoethylnitrile
    4 2-Oxopentylnitrile
    5 2-Oxo-3-methylbutylnitrile
    • Method 6 3-Amino-5-ethyl-1H-pyrazole
  • Hydrazine monohydrate (11.3g, 230mmol was added to a solution of 3-oxobutyronitrile (Method 2; 20.0g, 210mmol) in ethanol (50ml) and the mixture heated at 70°C for 12 hours. The volatiles were removed by evaporation and the residue was purified by column chromatography on silica gel eluting with DCM/methanol (90:10) to give the title compound as an oil. (10.2g, 44%). NMR (DMSO): 1.10 (t, 3H), 2.40 (q, 2H), 5.15 (s, 1H); m/z 112 (MH)+.
    • Methods 7 - 9
  • The following compounds were prepared by the procedure of Method 6 using the appropriate starting materials:
    Method Compound SM
    7 3-Amino-5-cyclopropyl-1H-pyrazole Method 3
    8 3-Amino-5-propyl-1H-pyrazole Method 4
    9 3-Amino-5-isopropyl-1H-pyrazole Method 5
    • Method 10 2,5-Dichloro-4-(5-methyl-1H-pyrrazol-3-ylamino)pyrimidine
  • A solution of 2,4,5-trichloropyrimidine (6.0g, 32.6mmol), 3-amino-5-methyl-1H-pyrrazole (3.18g, 32.7mmol) and N,N-diisopropylethylamine (6.30ml, 36.2mmol) in 1-butanol (50ml) was heated at 100°C for 2 hours. The volatiles were removed by evaporation and the residue was triturated with DCM to afford the title compound (5.7g, 72%) as a white solid. NMR (DMSO): 2.23 (s, 3H), 6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); m/z 290 (MH)+.
    • Methods 11 - 21
  • The following compounds were prepared by the procedure of Method 10 using the appropriate starting materials.
    Meth Compound SM
    11 5-Bromo-2-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine Meth 7
    12 5-Bromo-2-chloro-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine
    13 2,5-Dichloro-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine
    14 -5-Bromo-2-chloro-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine Meth 6
    15 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-chloropyrimidine
    16 2,5-Dichloro-4-(5-propyl-1H-pyrazol-3-ylamino)pyrimidine Meth 8
    17 2,5-Dichloro-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine Meth 6
    18 5-Bromo-4-(5-propyl-1H-pyrazol-3-ylamino)-2-chloropyrimidine Meth 8
    19 2,5-Dichloro-4-(5-isopropyl-1H-pyrazol-3-ylamino)pyrimidine Meth 9
    20 2,5-Dichloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine Meth 7
    21 5-Bromo-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-chloropyrimidine Meth 9
    • Method 22 α-Chlorobenzaldehyde oxime
  • N-chlorosuccinimide (5.50g, 41.3mmol) was added in portions to a solution of benzaldehyde oxime (5.0g, 41.3mmol) in DMF (34ml) such that the temperature did not rise above 35°C. The mixture was stirred at ambient temperature for 2 hours and then cooled witch an ice bath. Water was added and the aqueous mixture extracted with ether. The organics were combined, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation to give the title compound (6.43g, 100%) as an oil. NMR (CDCl3): 7.4 (m, 3H), 7.8 (d, 2H), 8.9 (bs, 1H).
    • Methods 23 - 33
  • The following compounds were prepared by the procedure of Method 22 using the appropriate starting materials.
    Method Compound SM
    23 1-chloro-2-methylpropylaldehyde oxime
    24 α-Chloro-2-methoxybenzaldehyde oxime
    25 α-Chloro-2-chlorobenzaldehyde oxime Method 36
    26 α-Chloro-2-fluorobenzaldehyde oxide Method 37
    27 α-Chloro-2-trifluoromethoxybenzaldehyde oxime Method 38
    28 α-Chloro-2-ethoxybenzaldehyde oxime Method 39
    29 α-Chloro-2-trifluoromethylbenzaldehyde oxime Method 40
    30 α-Chloro-2-methylbenzatdehyde oxime Method 41
    31 α-Chloro-2-bromobenzaldehyde oxime
    32 α-Chloro-2-methoxypyrid-3-ylcarbaldehyde oxime J.Chem. Soc. Perkin Trans 1 1990 2409-15.
    33 α-Chloro-3-methoxybenzaldehyde oxime Method 35
    • Method 34
  • α-Chloro-pyrid-3-ylcarbaldehyde oxime was prepared according to the method described in Tetrahedron 2000, 56, 1057-1064.
    • Method 35 3-Methoxybenzaldehyde oxime
  • A solution of hydroxylamine hydrochloride (10g, 0.144mol) in distilled water (20ml) was added to 20%(w/v) aqueous sodium hydroxide solution (28m). 3-Methoxybenzaldehyde (14ml, 0.12mol) was added in one portion and the mixture was stirred for 2 hours at 0-5°C. The mixture was adjusted to pH7 and extracted with dichloromethane. The extracts were combined, dried (MgSO4) and the solvent removed by evaporation to give the title compound (18.7g, 100%) as a colourless oil. NMR (CDCl3): 3.8 (s, 3H), 6.9 (m, 1H), 7.1 (m, 2H), 7.15 (m, 1H), 8.1 (s, 1H), 8.6 (br s, 1H).
    • Methods 36 - 42
  • The following compounds were prepared by the procedure of Method 35 using the appropriate starting materials.
    Method Compound
    36 2-chlorobenzaldehyde oxime
    37 2-fluorobenzaldehyde oxime
    38 2-trifluoromethoxybenzaldehyde oxime
    39 2-ethoxybenzaldehyde oxime
    40 2-trifluoromethylbenzaldehyde oxime
    41 2-methylbenzaldehyde oxime
    42 2-iodobenzaldehyde oxime
    • Method 43 5-(tert-Butoxycarbonylaminomethyl)-3-phenylisoxazole
  • A solution of α-chlorobenzaldehyde oxime (Method 22; 1g, 6.4mmol) in THF (13ml) was added dropwise to a solution of N-tert-butoxycarbonyl-propargylamine (0.5g, 3.2mmol) and triethylamine (0.9ml, 6.4mmol) in THF (25ml) cooled with an ice bath. The mixture was allowed to warm to ambient temperature and stirred for 2 days. The volatiles were removed by evaporation and the residue dissolved in DCM. The solution was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with isohexane/ether (9:1) and collected by filtration to give the title compound (473mg, 54%). NMR (CDCl3) 1.45 (s, 9H), 4.45 (d, 2H), 5.10 (bs, 1H), 6.5 (s, 1H), 7.42 (m, 3H), 7.8 (m, 2H).
    • Methods 44 - 55
  • The following compounds were prepared by the procedure of Method 43 using the appropriate starting materials.
    Meth Compound SM
    44 5-(tert-Butoxycarbonylaminomethyl)-3-isopropylisoxazole Meth 23
    45 5-(tert-Butoxycarbonylaminomethyl)-3-(2-methoxyphenyl)isoxazole Meth 24
    46 5-(tert-Butoxycarbonylaminomethyl)-3-(2-chlorophenyl)isoxazole Meth 25
    47 5-(tert-Butoxycarbonylaminomethyl)-3-(2-fluorophenyl)isoxazole Meth 26
    48 5-(tert-Butoxycarbonylaminomethyl)-3-(2-trifluoromethoxyphenyl)isoxazole Meth 27
    49 5-(tert-Butoxycarbonylaminomethyl)-3-(2-ethoxyphenyl)isoxazole Meth 28
    50 5-(tert-Butoxycarbonylaminomethyl)-3-(2-trifluoromethylphenyl)isoxazole Meth 29
    51 5-(tert-Butoxycarbonylaminomethyl)-3-(2-methylphenyl)isoxazole Meth 30
    52 5-(tert-Butoxycarbonylaminomethyl)-3-(2-bromophenyl)isoxazole Meth 31
    53 5-(tert-Butoxycarbonylaminomethyl)-3-(2-methoxypyrid-3-yl)isoxazole Meth 32
    54 5-(tert-Butoxycarbonylaminomethyl)-3-(3-methoxyphenyl)isoxazole Meth 33
    55 5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid-3-yl)isoxazole Meth 34
    • Method 56 5-Aminomethyl-3-phenylisoxazole
  • Trifluoroacetic acid (1.7ml, 2.6mmol) was added dropwise to a solution of 5-(tert-butoxycarbonylaminomethyl)-3-phenylisoxazole (Method 43; 473mg, 1.73mmol) in DCM (8ml) cooled in an ice bath. The mixture was warmed to ambient temperature and stirred for 18 hours and the volatiles removed by evaporation. The residue was triturated with ether to give the title compound (427mg, 86%). NMR (DMSO) 4.33 (s, 2H), 7.1 (s, 1H), 7.5 (m, 3H), 7.8 (m, 2H), 8.6 (br s, 3H).
    • Methods 57 - 68
  • The following compounds were prepared by the procedure of Method 56 using the appropriate starting materials.
    Method Compound Method
    57 5-Aminomethyl-3-isopropylisoxazole Method 44
    58 5-Aminomethyl-3-(2-methoxyphenyl)isoxazole Method 45
    59 5-Aminomethyl-3-(2-chlorophenyl)isoxazole Method 46
    60 5-Aminomethyl-3-(2-fluorophenyl)isoxazole Method 47
    61 5-Aminomethyl-3-(2-trifluoromethoxyphenyl)isoxazole Method 48
    62 5-Aminomethyl-3-(2-ethoxyphenyl)isoxazole Method 49
    63 5-Aminomethyl-3-(2-trifluoromethylphenyl)isoxazole Method 50
    64 5-Aminomethyl-3-(2-methylphenyl)isoxazole Method 51
    65 5-Aminomethyl-3-(2-bromophenyl)isoxazole Method 52
    66 5-Aminomethyl-3-(2-methoxypyrid-3-yl)isoxazole Method 53
    67 5-Aminomethyl-3-(3-methoxyphenyl)isoxazole Method 54
    68 5-Aminomethyl-3-(pyrid-3-yl)isoxazole Method 55
    • Method 69 5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid-2-yl)isoxazole
  • Sodium hypochlorite (16ml of a 14%w/v aqueous solution, 29.5mmol) was added dropwise to a solution of 2-pyridinealdoxime (2g, 16.4mmol) and N-tert-butoxycarbonyl-propargylamine (5.6g, 36.1 mmol) in DCM (30ml) cooled in an ice bath. The mixture was stirred vigorously and allowed to warm to ambient temperature and stirred for 18 hours. The aqueous layer was separated and extracted with DCM. The combined organic extracts were combined, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica gel eluting with diethyl ether/isohexane (1:1) to give the title compound (1.93g, 43%). NMR (CDCl3) 1.45 (s, 9H), 4.5 (m, 2H), 5.03 (bs, 1H), 6.8 (s, 1H), 7.35 (m, 1H), 7.8 (m, 1H), 8.05 (d, 1H), 8.67 (m, 1H).
    • Method 70 5-Aminomethyl-3-(pyrid-2-yl)isoxazole
  • 5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid-2-yl)isoxazole (Method 69) was treated as described in Method 56 to give 5-aminomethyl-3-(2-pyridyl)isoxazole. NMR (DMSO) 4.38 (s, 2H), 7.1 (s, 1H), 7.5 (m, 1H), 7.95 (m, 2H), 8.65 (br s, 3H), 8.7 (m, 1H).
    • Method 71 3-Methyl-5-(1-phthalamidoethyl)isoxazole
  • A solution of triethylamine (0.35ml, 2.5mmol) in toluene (15ml) was added dropwise to a solution of phenylisocyanate (5.43ml, 50mmol), nitroethane (2.15ml 30mmol) and N-(but-1-yn-3-yl)phthalamide (5.0g, 25mmol) in toluene (65ml) at ambient temperature. The mixture was stirred for 18 hours, filtered and the volatiles removed by evaporation. The residue was triturated with ether and the product collected by filtration to give the title compound (5.35g, 89%). NMR (CDCl3): 1.88 (d, 3H), 2.27 (s, 3H), 5.60 (q, H), 6.11 (s, H), 7.69-7.75 (m, 2H), 7.79-7.85 (m, 2H); m/z 257 (MH)+.
    • Method 72 5-(1-aminoethyl)-3-methylisoxazole
  • A mixture of the 3-methyl-5-(1-phthalamidoethyl)isoxazole (Method 71; 3.55g, 13.9mmol), hydrazine monohydrate (0.75ml, 15.3mmol) and ethanol (50ml) was heated at reflux for 4 hours. The mixture was allowed to cool to ambient temperature and glacial acetic acid (8.8ml, 153mmol) added, the mixture then heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature and the mixture neutralized with 50% aqueous sodium hydroxide solution, diluted with water and extracted with DCM, and the combined extracts washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was dissolved in ethanol and treated with an excess of IN ethereal hydrogen chloride, the volatiles removed by evaporation to give the title compound (1.52g, 87%). NMR (DMSO): 1.46 (dd, 3H), 2.20 (m, 3H), 4.39 (q H), 6.38 (s, 1H), 6.60 (br s, 3H); m/z 127 (MH)+.
    • Method 73 3-Ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole
  • A solution of ethyl chlorooximidoacetate (10g, 66mmol) in THF (200ml) was added dropwise over 3 hours to a mixture of N-(tert-butyloxycarbonyl)propargylamine (20.5g, 131mmol) and triethylamine (11.2ml, 80mmol) in tetrahyrofuran (100ml). The mixture was stirred at ambient temperature for 18 hours and then the volatiles were removed by evaporation. The residue was dissolved in DCM and washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica gel eluting with isohexane/diethyl ether (80:20 then 50:50) to give-the title compound (10.6g, 60%). NMR (DMSO): 1.3 (t, 3H), 1.38 (s, 9H), 4.35 (m, 2H), 6.62 (s, 1 H), 7.55 (s, 1 H); m/z 269 (M-H)-.
    • Method 74 3-Ethoxycarbonyl-5-aminomethylisoxazole
  • Trifluoroacetic acid (2.1 ml, 29mmol) was added to a solution of 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 790mg, 2.9mmol) in DCM (15ml). The mixture was stirred at ambient temperature for 4 hours then the volatiles removed by evaporation. The residue was triturated with diethyl ether to give the title compound (763g, 93%). NMR (DMSO): 1.31 (t, 3H), 4.37 (m, 2H), 6.97 (s, 1H), 8.64 (s, 3H); m/z 171 (MH)+.
    • Method 75 3-Hydroxymethyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole
  • Sodium borohydride (610mg, 16mmol) was added in portions to a solution of 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 1.62g, 6mmol) in ethanol (15ml) at 0°C under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 4 hours then quenched with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with EtOAc and the organics washed with brine then dried (MgSO4). The solvent was removed by evaporation to give the title compound (1.25g, 91%). NMR (DMSO): 1.38 (s, 9H), 4.21 (d, 2H), 4.44 (s, 2H), 5.40 (br s, I H), 6.21 (s, 1H), 7.49 (br s, 1H); m/z 229 (MH)+.
    • Method 76 3-Hydroxymethyl-5-aminomethylisoxazole
  • Trifluoroacetic acid (4ml, 54mmol) was added to a solution of 3-hydroxymethyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 75; 1.25g, 5.4mmol) in DCM (40ml). The mixture was stirred at ambient temperature for 18 hours then the volatiles removed by evaporation. The residue was purified by chromatography on a SCX-2 column (50g) eluting with methanol then 7N ammonia in methanol to give the title compound (676mg, 96%). NMR (DMSO): 1.97 (br s, 2H), 3.76 (s, 2H), 4.44 (s, 2H), 5.38 (s, 1H), 6.26 (s, 1H).
    • Method 77 3-(Pyrrolidin-1-ylcarbonyl)-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole
  • 3-Ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 500mg, 1.85mmol) was dissolved in pyrrolidine (4ml) and the mixture heated for 3 hours at 85°C. The volatiles were removed by evaporation and the residue was triturated with diethyl ether to give the title compound (432mg, 79%) as a white solid. NMR (DMSO): 1.38 (s, 9H), 1.85 (m, 4H), 3.50 (t, 2H), 3.62 (t, 2H), 4.29 (d, 2H), 6.47 (1H), 7.53 (s, 1H); m/z 240 (M-C4H8)+.
    • Method 78 3-(Pyrrolidin-1-ylcarbonyl)-5-aminomethyl]isoxazole
  • 3-(Pyrrolidin-1-ylcarbonyl)-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 77) was deprotected as described in Method 74 to give the title compound as its trifluoroacetate salt (428mg, 95%). NMR (DMSO): 1.88 (m, 4H), 3.49 (t, 2H), 3.63 (t, 2H), 4.35 (s, 2H), 6.83 (s, 1H), 8.58 (s, 3H); m/z 196 (MH)+.
    • Method 79 5-[N-(tert-Butoxycarbonyl)aminomethyl]-3-(2-iodoophenyl)isoxazole
  • 2-Iodobenzaldehyde oxime (Method 42) was treated as described in Methods 22 and 43 to give the title compound.
    • Method 80 5-[N-(tert-Butoxycarbonyl)aminomethyl]-3-(2-cyanophenyl)isoxazole
  • Copper (I) cyanide (2.49g, 27.8mmol), tetra-n-butylammoniumcyanide (1.87g, 6.95mmol), tris(dibenzylideneacetone)dipalladium(0) (0.247g, 0.28mmol) and diphenylphosphinoferrocene (0.619g, 1.12mmol) were added to a degassed solution of 5-[N-(tert-butoxycarbonyl)aminomethyl]-3-(2-iodoophenyl)isoxazole (Method 79; 2.78g, 6.95mmol) in 1,4-dioxan (35ml) under nitrogen. The mixture was heated at reflux for 3 hours, cooled to ambient temperature, diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexanes (15:85 increasing in polarity to 25:75) to give the title compound (1.29g, 62%). NMR (CDCl3): 1.49 (s, 9H), 4.52 (d, 2H), 5.09 (br s, H), 6.81 (s, H), 7.55 (t, H), 7.70 (t, H), 7.79 (d, H), 7.95 (d, H); m/z 300 (MH)+.
    • Method 81 5-Aminomethyl-3-(2-cyanophenyl)isoxazole
  • 5-[N-(tert-Butoxycarbonyl)aminomethyl]-3-(2-cyanophenyl)isoxazole (Method 80; 1.28g, 4.28mmol) was treated as described in Method 56 to give the title compound (1.34g, 100%). NMR (DMSO): 4.45 (s, 2H), 7.17 (s, H), 7.73 (dd, H), 7.85-7.95 (m, 2H), 8.62 (br s, 3H); m/z 200 (MH)+.
    • Method 82 3-Methyl-5-{2-[bis-(N-tert-butoxycarbonyl)aminolethyl]isoxazole
  • Bis-N-tert-butoxycarbonyl-3-butyne as synthesised in J. Am. Chem. Soc. 1987 (109), 2765 (2.2g, 8.2mmol), was treated as described in Method 71 to give the title compound (0.59g, 22%). NMR (CDCl3): 1.49 (s, 18H), 2.24 (s, 3H), 3.00 (t, 2H), 3.88 (t, 2H), 5.85 (s, H).
    • Method 83 3-Methyl-5-(2-aminoethyl)isoxazole
  • Trifluoroacetic acid (2.5ml, 3.8mmol) was added dropwise to a solution of 3-methyl-5-{2-[bis-(N-tert-butoxycarbonyl)amino]ethyl}isoxazole (Method 82; 0.589g, 1.8mmol) in DCM (10ml) cooled at 0°C. The mixture was allowed to warm to ambient temperature and stirred for 48 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on a SCX-2 ion exchange column eluting with methanol and then 7 N ammonia in methanol. The purified product was treated with an excess of 1.0M ethereal hydrogen chloride (3.5ml) to give the title compound as its hydrochloride salt (0.24g, 82%). NMR (DMSO) freebase: 2.18 (s, 3H), 2.71-2.79 (m, 2H), 2.80-2.88 (m, 2H), 6.10 (s, H).
    • Method 84 3-Azidomethyl-5-methylisoxazole
  • 3-Chloromethyl-5-methylisoxazole (500mg, 3.8mmol) and sodium azide (494mg 7.6mmol) were heated in DMF (10ml) at 60°C for 6 hours. The reaction mixture was diluted with water then extracted with EtOAc. The organic extracts were dried (MgSO4) and the volatiles removed by evaporation to give the title compound (387mg, 73%) as an oil. NMR (DMSO): 2.40 (s, 3H), 4.48 (s, 2H), 6.28 (s, 1H).
    • Method 85 3-Aminomethyl-5-methylisoxazole
  • 3-Azidomethyl-5-methylisoxazole (Method 84; 384mg, 2.8mmol) and polystyrene polymer supported triphenylphosphine (4.2g, 4.2mmol) were stirred together in a mixture of THF (17ml) and distilled water (0.58ml) for 24 hours. The reaction mixture was filtered, the resin washed with diethyl ether and then DCM. The combined filtrates were evaporated and the residue purified on a SCX-2 column eluting with methanol followed by 7N methanolic ammonia to give the title compound (211mg, 67%) as an oil. NMR (DMSO): 1.93 (br s, 2H), 2.34 (s, 3H), 3.63 (s, 2H), 6.17 (s, 1H).
    • Method 86 α-Methyl-pyridin-3-ylcarbaldehyde oxime
  • Hydroxylamine hydrochloride (9.46g, 136.2mmol) was added to a solution of 3-acetylpyridine (11.02g, 90.7mmol) in methanol (100ml) and the reaction mixture heated at reflux for 30 minutes. The volatiles were.removed by evaporation and the residue dissolved in water. The solution was cooled to 0°C and basified with 2N aqueous sodium hydroxide solution to pH 12 and the mixture then extracted with EtOAc. The extracts were combined, washed with saturated brine and dried (Na2SO4). The solvent was removed by evaporation to give the title product (11.6g, 94%) as a solid. NMR (DMSO): 2.20 (s, 3H), 7.40 (m, 1H), 8.00 (m, 1H), 8.55 (d, 1H), 8.85 (s, 1H) 11.43 (s, 1H), m/z: 137 (MH)+.
    • Methods 87 - 89
  • The following compounds were prepared by the procedure of Method 86 using the appropriate starting materials.
    Method Compound
    87 α-Methyl-pyridin-2-ylcarbaldehyde oxime
    88 α-Ethyl-pyridin-2-ylcarbaldehyde oxime
    89 α-Ethyl-pyridin-3-ylcarbaldehyde oxime
    • Method 90 3-(1-Aminoethyl)pyridine
  • A 50% suspension of rainey nickel in water (1.1g) was added to a solution of α-methyl-pyridin-3-ylcarbaldehyde oxime (Method 86; 10.6g, 77.9mmol) and 20% ethanolic ammonia (500ml) and the reaction mixture hydrogenated with gaseous hydrogen at 40 psi and 40°C until the theoretical volume of gas was consumed. The reaction mixture was filtered through a layer of diatomaceous earth and the filter pad washed with water and ethanol. The filtrate was removed by evaporation of give the title product. (8.05g, 85%) as an oil. NMR (DMSO): 1.28 (d, 3H), 4.05 (m, 1H), 7.33 (t, 1H), 7.75 (d, 1H), 8.40 (d, 1H), 8.55 (s, 1H), m/z: 123 (MH)+.
    • Methods 91 - 93
  • The following compounds were prepared by the procedure of Method 90 using the appropriate starting materials.
    Method Compound SM
    91 2-(1-Aminoethyl)pyridine Method 87
    92 2-(1-Aminopropyl)pyridine Method 88
    93 3-(1-Aminopropyl)pyridine Method 89
    • Method 94 2-Aminomethyl-6-chloropyridine
  • A 1M solution of lithium aluminium hydride in THF (2.88ml, 2.88mmol) was added dropwise to a solution of 6-chloro-2-cyanopyridine (532mg, 3.84mmol) in THF (10ml) at - 5°C under an atmosphere of nitrogen. The mixture was stirred at -5°C for two hours and the reaction quenched by careful, sequential addition of water (0.1 ml), 15% aqueous sodium hydroxide solution (0.1ml) and then water (0.3ml). The mixture was stirred for one hour at 0°C, the insolubles removed by filtration and the filter pad washed thoroughly with methanol. The resulting solution was evaporated and the residue purified by column chromatography on silica gel eluting with DC-M/methanol/ammonia (95:5:0 increasing in polarity to 90: 10: 1) to give-the title compound. (215mg, 40%) as an oil. NMR (DMSO): 2.10 (br s, 2H), 3.75 (s, 2H), 7.30 (d, 1H), 7.55 (d, 1H), 7.80 (t, 1H).
    • Methods 95 - 97
  • The following compounds were prepared by the procedure of Method 94 using the appropriate starting materials.
    Method Compound
    95 2-Aminomethyl-6-methylpyridine
    961 2-Aminomethyl-5,6-dimethylpyridine
    97 2-Aminomethyl-3-methylpyridine
    1 SM Bioorg. Med. Chem. Lett. 1998, 453-8
    • Method 98 2-(N-Oxopyridin-4-yl)pyridine
  • 3-Chloroperbenzoic acid (57%-86% active strength) (7.5g,43mmol) was added in portions to a solution of 2-(pyridin-4-yl)pyridine (4.78g, 30.6mmol) in DCM (50ml) at 0°C. After stirring for 2 hours sodium metabisulfite was added in portions until all excess peroxide was destroyed. The solids were removed by filtration and the filtrate was basified with solid potassium carbonate. The mixture was filtered, the filtrate evaporated and the residue purified by column chromatography on silica gel eluting with methanol/acetone (10:90) to give the title compound (4.2g; 80%) as a white solid. NMR (DMSO): 7.41 (t, 1H), 7.92 (t, 1H), 8.10 (m, 3H), 8.30 (d, 2H), 8.70 (d, 1H); m/z 173 (MH)+.
    • Method 99 2-(2-Cyanopyridin-4-yl)pyridine
  • Trimethylsilylcyanide (1.9ml, 14.5mmol) was added dropwise to a suspension of 2-(N-oxopyridin-4-yl)pyridine (Method 98; 1g, 5.8mmol) and triethylamine (1.2ml, 8.7mmol) in acetonitrile (5ml). The mixture was heated at 110°C for 18 hours, cooled to ambient temperature then diluted with aqueous saturated sodium hydrogen carbonate solution. The mixture was extracted with DCM, the extracts dried (MgSO4) and the volatiles removed by evaporation. The residue was pre-adsorbed onto silica and purified by column chromatography on silica gel eluting with hexane:EtOAc (1:1). The purified product was triturated with diethyl ether to give the title compound (627mg, 60%) as a white solid NMR (DMSO): 7.54 (t, 1 H), 8.01 (t, 1H), 8.25 (d, 1H), 8.40 (d, 1H), 8.66 (s, 1H), 8.77 (d, 1H), 8.87 (d, 1H).
    • Method 100 2-(2-Aminomethylpyridin-4-yl)pyridine
  • 2-(2-Cyanopyridin-4-yl)pyridine (Method 99; 563mg, 3.11 mmol) was dissolved in anhydrous THF (10ml) under a nitrogen atmosphere and was cooled to 0°C. LiAlH4 (2.3ml of a 1M solution in THF, 2.3mmol) was added dropwise and the reaction was stirred at 0°C for 3 hours. The reaction was quenched with water (0.1 ml) followed by 15% sodium hydroxide solution (0.1 ml) then water (0.3ml). The mixture was filtered and the filter pad was washed with methanol. The volatiles were removed from the filtrate by evaporation to give the title compound (570mg, 99%) as a gum. m/z 186 (MH)+
    • Method 101 2-(3-Cyanopyridin-5-yl)pyridine
  • 2-(3-Bromopyridin-5-yl)pyridine (2g, 10.9mmol) in THF (10ml) was added dropwise to a solution of 2-pyridylzincbromide (22ml of a 0.5M solution in THF, 11 mmol) in THF (10ml) under a nitrogen atmosphere. Tetrakis (triphenylphosphine)palladium(0) (630mg, 0.54mmol) was added and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride solution then the volatiles were removed by evaporation. The residue was suspended in water then extracted with DCM. The organic extracts were combined, washed with water then filtered through phase separating paper and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane:EtOAc (2:1). The purified product was triturated with diethyl ether to give the title compound (0.98g, 50%) as a white solid. NMR (DMSO): 7.47 (t, 1H), 7.97 (t, 1H), 8.15 (d; 1H), 8.75 (d, 1H), 8.90 (d, 1H), 9.07 (s, 1H), 9.53 (s, 1H); m/z 182 (MH)+.
    • Method 102 2-(3-Aminomethylpyridin-5-yl)pyridine
  • 2-(3-Cyanopyridin-5-yl)pyridine (Method 101; 0.98g, 5.4mmol) was dissolved in a mixture of ethanol (45ml) and methanol (30ml). Concentrated hydrochloric acid (1.2ml) and 10% palladium on carbon catalyst (575mg) were added and the mixture stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth, the filter pad washed with ethanol and the volatiles removed from the filtrate by evaporation. The crude solid was suspended in a small volume of methanol and filtered to give the title compound (794mg, 66%) as an orange solid. NMR (DMSO): 4.31 (m, 2H) 7.58 (t, 1H), 8.09 (t, 1H), 8.24 (d, 1H), 8.78 (d, 1H), 8.89 (bs, 2H), 9.03 (s, 1H), 9.26 (s, 1H), 9.43 (s, 1H); m/z 186 (MH)+.
    • Pharmacological Analysis Methods For Detecting Inhibition Of Igf-1r Kinase Activity And Downstream Signalling And Selectivity Over Insulin Receptor Kinase And Egfr Signalling Abbreviations used
    • PBS (PBS/T) is Phosphate buffered saline, pH7.4 (with 0.05% Tween 20)
    • HEPES is N-[2-Hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]
    • DTT is dithiothreitol
    • TMB is tetramethyl benzidine
    • DMSO is dimethyl sulphoxide
    • BSA is bovine serum albumin
    • ATP is adenosine tri-phosphate
    • DMEM is Dulbecco's modified Eagle's Medium
    • FBS/FCS is foetal bovine/calf serum
    • HBSS is Hanks Balanced Salts Solution
    • HRP is horse-radish peroxidase
    • SDS is sodium dodecyl sulphate
    • IGF-I (IGF-1R) is insulin-like growth factor-I (IGF-1 receptor)
    • EGF is Epidermal growth factor
    IGF-1R Kinase Assay a) Protein cloning, expression and purification
  • A DNA molecule encoding a fusion protein containing glutathione-S-transferase (GST), thrombin cleavage site and IGF-1R intracellular domain (amino-acids 930-1367) and subsequently referred to as GST-IGFR, was constructed and cloned into pFastBacl (Life Technologies Ltd, UK) using standard molecular biology techniques (Molecular Cloning - A Laboratory Manual, Second Edition 1989; Sambrook, Fritsch and Maniatis; Cold Spring Harbour Laboratory Press).
  • Production of recombinant virus was performed following the manufacturer's protocol. Briefly, the pFastBac-1 vector containing GST-IGFR was transformed into E. coli DH10Bac cells containing the baculovirus genome (bacmid DNA) and via a transposition event in the cells, a region of the pFastBac vector containing gentamycin resistance gene and the GST-IGFR expression cassette including the baculovirus polyhedrin promoter was transposed directly into the bacmid DNA. By selection on gentamycin, kanamycin, tetracycline and X-gal, resultant white colonies should contain recombinant bacmid DNA encoding GST-IGFR. Bacmid DNA was extracted from a small scale culture of several BH10Bac white colonies and transfected into Spodoptera frugiperda Sf21 cells grown in TC100 medium (Life Technologies Ltd, UK) containing 10% serum using CellFECTIN reagent (Life Technologies Ltd, UK) following the manufacturer's instructions. Virus particles were harvested by collecting cell culture medium 72 hrs post transfection. 0.5 mls of medium was used to infect 100 ml suspension culture of Sf21s containing 1 x 107 cells/ml. Cell culture medium was harvested 48 hrs post infection and virus titre determined using a standard plaque assay procedure. Virus stocks were used to infect Sf9 and "High 5" cells at a multiplicity of infection (MOI) of 3 to ascertain expression of recombinant GST-IGFR.
  • The GST-IGFR protein was purified by affinity chromatography on Glutathione-Sepharose followed by elution with glutathione. Briefly, cells were lysed in 50mM HEPES pH 7.5 (Sigma, H3375), 200mM NaCl (Sigma, S7653), Complete Protease Inhibitor cocktail (Roche, 1 873 580) and 1mM DTT (Sigma, D9779), hereinafter referred to as lysis buffer. Clarified lysate supernatant was loaded through a chromatography column packed with Glutathione Sepharose (Amersham Pharmacia Biotech UK Ltd.). Contaminants were washed from the matrix with lysis buffer until the UV absorbance at 280nm returned to the baseline. Elution was carried out with lysis buffer containing 20mM reduced glutathione (Sigma, D2804) and fractions containing the GST fusion protein were pooled and dialysed into a glycerol-containing buffer comprising 50 mM HEPES, pH 7.5, 200 mM NaCl, 10% glycerol (v/v), 3 mM reduced glutathione and 1 mM DTT.
    • b) Kinase activity assay
  • The activity of the purified enzyme was measured by phosphorylation of a synthetic poly GluAlaTyr (EAY) 6:3:1 peptide (Sigma-Aldrich Company Ltd, UK, P3899) using an ELISA detection system in a 96-well format
    • b.i) Reagents used Stock solutions
  • 200mM HEPES, pH 7.4 stored at 4°C (Sigma, H337.5)
    1M DTT stored at -20°C (Sigma, D9779)
    100mM Na3 VO4 stored at 4°C (Sigma, S6508)
    1M MnCl2 stored at 4°C (Sigma, M3634)
    1 mM ATP stored at -20°C (Sigma, A3377)
    Neat Triton X-100 stored at room temperature (Sigma, T9284)
    10mg/ml BSA stored at 4°C (Sigma, A7888)
    • Enzyme solution
  • GST-IGF-1R fusion protein at 75ng/ml in 100mM HEPES, pH 7.4, 5mM DTT, 0.25mM Na3VO4, 0.25% Triton X-100, 0.25mg/ml BSA, freshly prepared.
    • Co-factor solution
  • 100mM HEPES, pH 7.4, 60mM MnCl2, 5mM ATP
    • Poly EAY substrate
  • Sigma substrate poly (Glu, Ala, Tyr) 6:3:1 (P3899)
    Made up to 1 mg/ml in PBS and stored at -20°C
    • Assay plates
  • Nunc Maxisorp 96 well immunoplates (Life Technologies Ltd, UK)
    • Antibodies
  • Anti-phosphotyrosine antibody, monoclonal from Upstate Biotechnology Inc., NY, USA (UBI 05-321). Dilute 3µl in 11 ml PBS/T + 0.5% BSA per assay plate.
  • Sheep- anti-mouse IgG HRP-conjugated secondary antibody from Amersham Pharmacia Biotech UK Ltd. (NXA931). Dilute 20µl of stock into 11 ml PBS/T + 0.5% BSA per assay plate.
    • TMB solution
  • Dissolve 1mg TMB tablet (Sigma T5525) into 1ml DMSO (Sigma, D8779) in the dark for 1 hour at room temperature. Add this solution to 9ml of freshly prepared 50mM phosphate-citrate buffer pH 5.0 + 0.03% sodium perborate [1 buffer capsule (Sigma P4922) per 100ml distilled water].
  • Stop solution is 1M H2SO4 (Fisher Scientific UK. Cat. No. S/9200/PB08).
    • Test compound
  • Dissolve in DMSO to 10mM then dilutions in distilled water to give a range from 200 to 0.0026µM in 1-2% DMSO final concentration in assay well.
    • b.ii) Assay protocol
  • The poly EAY substrate was diluted to 1µg/ml in PBS and then dispensed in an amount of 100µl per well into a 96-well plate. The plate was sealed and incubated overnight at 4°C. Excess poly EAY solution was discarded and the plate was washed (2x PBS/.T; 250µl PBS per well), blotting dry between washes. The plate was then washed again (1x 50mM HEPES, pH.7.4; 250µl per well) and blotted dry (this is important in order to remove background phosphate levels). 100µl test compound solution was added with 40µl of kinase solution to each well. Then 50µl of co-factor solution were added to each well and the plate was incubated for 60 minutes at room temperature.
  • The plate was emptied (i.e. the contents were discarded) and was washed twice with PBS/T (250µl per well), blotting dry between each wash. 100µl of diluted anti-phosphotyrosine antibody were added per well and the plate was incubated for 60 minutes at room temperature.
  • The plate was again emptied and washed twice with PBS/T (250µl per well), blotting dry between each wash. 100µl of diluted sheep- anti-mouse IgG antibody were added per well and the plate was left for 60 minutes at room temperature. The contents were discarded and the plate washed twice with PBS/T (250µl per well), blotting dry between each wash. 100µl of TMB solution were added per well and the plate was incubated for 5-10 minutes at room temperature (solution turns blue in the presence horse radish peroxidase).
  • Reaction was stopped with 50µl of H2SO4 per well (turns the blue solution yellow) and the plate was read at 450nm in Versamax plate reader (Molecular Devices Corporation, CA, USA) or similar.
  • The compounds of the Examples were found to have an IC50 in the above test of less than 100µM.
    • Inhibition of IGF-stimulated cell proliferation
  • The construction of murine fibroblasts (NIH3T3) over-expressing human IGF-1 receptor has been described by Lammers et al (EMBO J, 8, 1369-1375, 1989). These cells show a proliferative response to IGF-I which can be measured by BrdU incorporation into newly synthesised DNA. Compound potency was determined as causing inhibition of the IGF-stimulated proliferation in the following assay:
    • a.i) Reagents used:
    • Cell Proliferation ELISA, BrdU (colorimetric) [Boehringer Mannheim (Diagnostics and Biochemicals) Ltd, UK. Cat no. 1 647 229].
    • DMEM, FCS, Glutamine, HBSS (all from Life Technologies Ltd., UK).
    • Charcoal/Dextran Stripped FBS (HyClone SH30068.02, Perbio Science UK Ltd).
    • BSA (Sigma, A7888).
    • Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78 008 176 298, Australia. Cat No. IU 100).
    Preparation And Storage Of IGF
    • 100µg of lyophilised IGF was reconstituted in 100ul of 10mM HCl.
    • Add 400µl of 1mg/ml BSA in PBS
    • 25µl aliquots @ 200µg/ml IGF-1
    • Stored at -20°C
    For Assay:
    • 10µl of stock IGF + 1-2.5ml growth medium to give 8X stock of 160ng/ml.
    Complete growth medium
  • DMEM, 10% FCS, 2mM glutamine
    • Starvation medium
  • DMEM, 1 % charcoal/dextran stripped FCS, 2mM glutamine
    • Test Compound
  • Compounds are initially dissolved in DMSO to 10mM, followed by dilutions in DMEM + 1% FCS + glutamine to give a range from 100 to 0.0.45µM in 1- 0.00045% DMSO final concentration in assay well
    • a.ii) Assay protocol Day 1
  • Exponentially growing NIH3T3/IGFR cells were harvested and seeded in complete growth medium into a flat-bottomed 96 well tissue culture grade plate (Costar 3525) at 1.2x 104 cells per well in a volume of 100µl.
    • Day 2
  • Growth medium was carefully removed from each well using a multi-channel pipette. Wells were carefully rinsed three times with 200µl with HBSS. 100µl of starvation medium was added to each well and the platewas re-incubated for 24 hours. Day 3
  • 50µl of a 4X concentrate of test compound was added to appropriate wells. Cells were incubated for 30 minutes with compound alone before the addition of IGF. For cells treated with IGF, an appropriate volume (ie. 25µl) of starvation medium was added to make a final volume per well up to 200µl followed by 25µl of IGF-1 at 160ng/ml (to give a final concentration of 20ng/ml). Control cells unstimulated with IGF also had an appropriate volume (ie. 50µl) of starvation medium added to make final volume per well up to 200µl. The plate was re-incubated for 20 hours.
    • Day 4
  • The incorporation of BrdU in the cells (after a 4h incorporation period) was assessed using the BrdU Cell Proliferation Elisa according to the manufacturer's protocol.
  • The compounds of the Examples were found to have an IC50 in the above test of less than 50µM.
    • Mechanism of Action Assay
  • Inhibition of IGF-IR mediated signal transduction was determined by measuring changes in phosphorylation of IGF-IR, Akt and MAPK (ERK1 and 2) in response to IGF-I stimulation of MCF-7 cells (ATCC No. HTB-22). A measure of selectivity was provided by the effect on MAPK phosphorylation in response to EGF in the same cell line.
    • a.i) Reagents used:
    • RPMI 1640 medium, RPMI 1640 medium without Phenol Red, FCS, Glutamine (all from Life Technologies Ltd., UK)
    • Charcoal/Dextran Stripped FBS (HyClone SH30068.02, Perbio Science UK Ltd)
    • SDS (Sigma, LA390)
    • 2-mercaptoethanol (Sigma, M6250)
    • Bromophenol blue (Sigma, B5525)
    • Ponceau S (Sigma, P3504)
    • Tris base (TRIZMA™ base, Sigma, T1503)
    • Glycine (Sigma, G7403)
    • Methanol (Fisher Scientific UK. Cat. No. M/3950/21)
    • Dried milk powder (Marvel™, Premier Brands UK Ltd.)
    • Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78 008 176 298, Australia. Cat No. IU 100).
    • Human recombinant EGF (Promega Corporation, WI, USA. Cat. No. G5021)
    Complete growth medium
  • RPMI 1640, 10% FCS, 2mM glutamine
    • Starvation medium
  • RPMI1640 medium without Phenol Red, 1% charcoal/dextran stripped FCS, 2mM glutamine
    • Test Compound
  • Compounds were initially dissolved in DMSO to 10mM, followed by dilutions in RPMI 1640 medium without Phenol Red + 1% FCS + 2mM glutamine to give a range from 100 to 0.0.45µM in 1- 0.00045% DMSO final concentration in assay well.
    • Western transfer buffer
  • 50mM Tris base, 40mM glycine, 0.04% SDS, 20% methanol
    • Laemmli buffer x2:
  • 100mM Tris-HCl pH6.8, 20% glycerol, 4% SDS
    • Sample buffer x4:
  • 200mM 2-mercaptoethanol, 0.2% bromophenol blue in distilled water.
    • Primary Antibodies
  • Rabbit anti-human IGF-1Rβ (Santa Cruz Biotechnology Inc., USA, Cat. No sc-713)
  • Rabbit anti-insulin/IGF-1R [pYpY1162/1163] Dual Phosphospecific (BioSource International Inc, CA, USA. Cat No. 44-8041)
  • Mouse anti-PKBα/Akt (Transduction Laboratories, KY, USA. Cat. No. P67220)
  • Rabbit anti-Phospho-Akt (Ser473) (Cell Signalling Technology Inc, MA, USA. Cat. No.#9271)
  • Rabbit anti-p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA. Cat. No.#9102)
  • Rabbit anti-Phospho p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA. Cat. No.#9101)
  • Mouse anti-actin clone AC-40 (Sigma-Aldrich Company Ltd, UK, A4700) Antibody dilutions
    Antibody Dilution in PBST Secondary antibody in PBST
    IGFR 1:200 with 5% milk Anti-rabbit with 5% milk
    Phospho-IGFR 1:1000 with 5% milk Anti-rabbit with 5% milk
    Akt 1:1000 with 5% milk Anti-mouse with 5% milk
    PhosphoAkt 1:1000 with 5% milk Anti-rabbit with 5% milk
    MAPK 1:1000 with 5% milk Anti-rabbit with 5% milk
    Phospho-MAPK 1:1000 with 5% milk Anti-rabbit with 5% milk
    Actin 1:1000 with 5% milk Anti-mouse with 5% milk
    • Secondary antibodies
  • Goat anti-rabbit, HRP linked (Cell Signalling Technology Inc, MA, USA. Cat. No.#7074)
  • Sheep- anti-mouse IgG HRP-conjugated (Amersham Pharmacia Biotech UK Ltd. Cat. No. NXA931)
  • Dilute anti-rabbit to 1:2000 in PBST + 5% milk
  • Dilute anti-mouse to 1:5000 in PBST + 5% milk
    • a.ii) Assay Protocol Cell treatment
  • MCF-7 cells were plated out in a 24 well plate at 1x 105 cells/well in 1ml complete growth medium. The plate was incubated four 24 hours to allow the cells to settle. The medium was removed and the plate was washed gently 3 times with PBS 2ml/well. 1ml of starvation medium was added to each well and the plate was incubated for 24 hours to serum starve the cells.
  • Then 25µl of each compound dilution was added and the cells and compound were incubated for 30 minutes at 37°C. After 30 minutes incubation of the compound, 25µl of IGF (for 20ng/ml final concentration) or EGF (for 0.1 ng/ml final concentration) was added to each well as appropriate and the cells incubated with the IGF or EGF for 5 minutes at 37°C. The medium was removed (by pipetting) and then 100µl of 2x Laemmli buffer was added. The plates were stored at 4°C until the cells were harvested. (Harvesting should occur within 2. hours following addition of Laemmli buffer to the cells.)
  • To harvest the cells, a pipette was used to repeatedly draw up and expel the Laemmli buffer/cell mix and transfer into a 1.5ml Eppendorf tube. The harvested cell lysates were kept at -20°C until required. The protein concentration of each lysate could be determined using the DC protein assay kit (Bio-Rad Laboratories, USA, according to manufacturer's instructions).
    • Western blot technique
  • Cell samples were made up with 4x sample buffer, syringed with a 21 gauge needle and boiled for 5 minutes. Samples were loaded at equal volumes and a molecular weight ladder on 4-12% Bis-Tris gels (Invitrogen BV, The Netherlands) and the gels were run in an Xcell SureLock ™ Mini-Cell apparatus (Invitrogen) with the solutions provided and according to the manufacturer's instructions. The gels were blotted onto Hybond C Extra™ membrane (Amersham Pharmacia Biotech UK Ltd.) for 1 hour at 30 volts in the Xcell SureLock ™ Mini-Cell apparatus, using Western transfer buffer. The blotted membranes were stained with 0.1% Ponceau S to visualise transferred proteins and then cut into strips horizontally for multiple antibody incubations according to the molecular weight standards. Separate strips were used for detection of IGF-1R, Akt, MAPK and actin control.
  • The membranes were blocked for 1 hour at room temperature in PBST + 5% milk solution. The membranes were then placed into 3ml primary antibody solution in 4 well plates and the plates were incubated overnight at 4°C. The membranes were washed in 5ml PBST, 3 times for 5 minutes each wash. The HRP-conjugated secondary antibody solution was prepared and 5ml was added per membrane. The membranes were incubated for 1 hour at room temperature with agitation. The membranes were washed in 5ml PBST, 3 times for 5 minutes each wash. The ECL solution (supersignal ECL, Pierce, Perbio Science UK Ltd) was prepared and incubated with the membranes for 1 minute (according to manufacturer's instructions), followed by exposure to light sensitive film and development.
  • The compounds of the Examples were found to have an IC50 in the above test of lessthan 20µM.

Claims (24)

  1. A compound of formula (I):
    Figure imgb0007
     wherein
    R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at-least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR-5R6, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(O)mC1-C6alkyl, -C(O)NR7R8, -SO2NR7aR8a, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring itself being optionally_substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR9R10, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylamino, phenylcarbonyl, -S(O)nC1-C6alkyl, -C(O)NR11R12 and -SO2NR11aR12a;
    m is 0, 1 or 2;
    n is 0, 1 or 2;
    R2 represents a C1-C4alkyl group optionally substituted by at least one substituent selected from halogen, hydroxyl and C1-C3alkoxy;
    R3 represents hydrogen, halogen or trifluoromethyl;
    R4 represents a 5-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR13R14, carboxyl, hydroxyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C4alkoxycarbonyl, C1-C4alkylcarbonyl, C1-C4alkylcarbonylamino, phenylcarbonyl, -S(O)pC1-C4alkyl, -C(O)NR15R16 and -SO2NR15aR16a;
    p is 0, 1 or 2;
    R5 and R6 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R7 and R8 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R7a and R8a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R7a and R8a together with the nitrogen atom to which they are attached form a 4 to 6-membered saturated heterocycle;
    R9 and R10 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R11 and R12 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R11a and R12a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R11a and R12a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R13 and R14 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    R15 and R16 each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; and
    R15a and R16a each independently represent hydrogen, C1-C4alkyl or C3-C6cycloalkyl, or R15a and R16a together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle;
    or a pharmaceutically acceptable salt or solvate thereof.
  2. A compound according to claim 1, wherein, R1 represents a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from hydroxyl), halogen, -C(O)NR7R8, C1-C6alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen and oxygen, the ring itself being optionally substituted by at least one - substituents selected from C1-C6alkyl, C1-C6alkoxy (each of which may be optionally substituted by at least one substituent selected from halogen), halogen and cyano; wherein R7 and R8 are both hydrogen or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; or a pharmaceutically acceptable salt or solvate thereof.
  3. A compound according to claim 1 or claim 2, wherein R1 represents pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl or Thienyl; said pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl and thienyl being optionally substituted by at least one substituent selected from methyl, isopropyl, hydroxymethyl, methoxy, chloro, bromo, carbamoyl, methoxycarbonyl, pyrrolidin-1-ylcarbonyl, phenyl and pyridyl; said phenyl or pyridyl being optionally substituted by at least one substituent selected from methyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, fluoro, chloro, bromo and cyano; or a pharmaceutically acceptable salt or solvate thereof.
  4. A compound according to any one of claims 1 to 3, wherein R2 represents a C1-C4alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
  5. A compound according to any one of claims 1 to 4, wherein R3 represents hydrogen or halogen; or a pharmaceutically acceptable salt or solvate thereof.
  6. A compound according to any one of claims to 5, wherein, R4 represents a 5-membered heteroaromatic ring comprising art least one ring heteroatom selected from nitrogen, the ring being optionally substituted by at least one substituent selected from C1-C6alkyl and C3-C6cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.
  7. A compound according to claim 6, wherein, in R4, the 5-membered heteroaromatic ring is pyrazolyl, the ring being optionally substituted by at least one substituent selected from methyl, ethyl, isopropyl, propyl, t-butyl and cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof.
  8. A compound according to claim 1, wherein
    R1 represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid-5-yl, 2-cyanopyrid-5-yl, 3-bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-yl, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-yl, 6-methylpyrid-2-yl, 5,6-dimethylpyrid-2-yl, imidazol-4-yl, imidazol-5-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl, 3-methoxycarbonylisoxazol-5-yl, 3-(hydroxymethyl)isoxazol-5-yl, 3-carbamoylisoxazol-5-yl, 3-(pyrrolidin-1-ylcarbonyl)isoxazol-5-yl, 3-phenylisoxazol-5-yl, 3-(pyrid-2-yl)isoxazol-5-yl, 3-(2-methoxypyrid-3-yl)isoxazol-5-yl, 3-(2-methoxyphenyl)isoxazol-5-yl, 3-(3-methoxyphenyl)isoxazol-5-yl, 3-(2-ethoxyphenyl)isoxazol-5-yl, 3-(2-trifluoromethylphenyl)isoxazol-5-yl, 3-(2-trifluoromethoxyphenyl)isoxazol-5-yl, 3-(2-chlorophenyl)isoxazol-5-yl, 3-(2-bromophenyl)isoxazol-5-yl, 3-(2-methylphenyl)isoxazol-5-yl, 3-(2-fluorophenyl)isoxazol-5-yl, 3-(2-cyanophenyl)isoxazol-5-yl, 5-methylpyrazol-4-yl, fur-2-yl, fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl-, 2-methylpyrazin-5-yl, pyridazin-3-yl, pyrimidin-4-yl, 1-methylpyrrol-2-yl and thien-3-yl;
    R2 represents methyl, ethyl and propyl;
    R3 represents hydrogen, chloro or bromo; and
    R4 represents 5-methylpyrazol-3-yl, 5-ethylpyrazol-3-yl, 5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl, 5-t-butylpyrazol-3-yl and 5-cyclopropylpyrazol-3-yl;
    or a pharmaceutically acceptable salt or solvate thereof.
  9. A compound according to claim 1 selected from:
    5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-cyclopropyl- 1H-pyrazol-3-ylamino)pyrimidine,
    5-Chloro-2-(3-phenylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Chloro-2-(3-pyrid-2-ylisoxazol-5-yl-methylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Bromo-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Chloro-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Bromo-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Chloro-2-[3-(2-fluorophenyl)isoxazol-5-ylmethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Bromo-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-(pyrid-2-ylmethylamino) pyrimidine,
    5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-propyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-isopropyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Chloro-2-[3-(pyrid-2-yl)isoicazol-5-ylmethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    5-Bromo-2-[3-(pyrid-2-yl)isoxazol-5-ylmethylamino]-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine, and
    5-Bromo-2-(3-bromopyrid-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,
    and pharmaceutically acceptable salts and solvates of any one thereof.
  10. A process for the preparation of a compound according to claim 1, which comprises:
    (i) reacting a compound of formula
    Figure imgb0008
     wherein L1 represents a leaving group and R3 and R4 are as defined in formula (I), with a compound of formula (III), H2N-R2-R1, wherein R1 and R2 are as defined in formula (I); or
    (ii) reacting a compound of formula
    Figure imgb0009
     wherein L2 represents a leaving group and R1, R2 and R3 are as defined in formula (I), with a compound of formula (V), H2N-R4, wherein R4 is as defined in formula (I); or
    (iii) reacting a compound of formula
    Figure imgb0010
     wherein R1 and R2 are as defined in formula (I), with a compound of formula
    Figure imgb0011
     wherein X represents an oxygen atom and q is 1 or X represents a nitrogen atom and q is 2, each R20 independently represents a C1-C6alkyl group and R3 and R4 are as defined in formula (I); or
    (iv) when R4 represents a substituted pyrazolyl, reacting a compound of formula
    Figure imgb0012
    wherein R21 represents a C1-C6alkyl or C3-C6cycloalkyl group and R1, R2 and R3 are as defined in formula (I) with hydrazine;
    and optionally after (i), (ii), (iii) or (iv) carrying out one or more of the following:
    • converting the compound obtained to a further compound according to claim 1
    • forming a pharmaceutically acceptable salt or solvate of the compound
  11. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  12. A process for the preparation of a pharmaceutical composition as claimed in claim 11 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 9 with a pharmaceutically acceptable adjuvant, diluent or carrier.
  13. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 for use in therapy.
  14. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 in the manufacture of a medicament for use in the treatment of cancer.
  15. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 in the manufacture of a medicament for use in modulating insulin-like growth factor-1 receptor activity.
  16. Compounds of formula (I) for use in the treatment of cancer which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9.
  17. Compounds of formula (I) for use in the modulation of insulin-like growth factor-1 receptor activity which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9.
  18. A compound according to claim 1, wherein, in R1, the 5- or 6-membered heteroaromatic ring is selected from thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof.
  19. A compound according to claim 1, wherein, in R1, the 5- or 6-membered heteroaromatic ring is selected from thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof.
  20. A compound according to claim 1, wherein, in R1, the unsaturated 5- to 6-membered ring is selected from phenyl, cylopentenyl, cyclohexenyl, thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof.
  21. A compound according to claim 1, wherein, in R1, the unsaturated 5- to 6-membered ring is selected from phenyl, cylopentenyl, cyclohexenyl, thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl and pyridyl; or a pharmaceutically acceptable salt or solvate thereof.
  22. A compound according to claim 1, wherein R3 represents a halogen atom; or a pharmaceutically acceptable salt or solvate thereof.
  23. A compound according to claim 1, wherein, in R4, the 5-membered heteroaromatic ring is selected from thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl and imidazolyl; or a pharmaceutically acceptable salt or solvate thereof.
  24. A compound according to claim 1, wherein, in R4, the 5-membered heteroaromatic ring is pyrazolyl; or a pharmaceutically acceptable salt or solvate thereof.
EP02791165A 2001-12-07 2002-12-03 Pyrimidine derivatives as modulators of insuline-like growth factor-1 receptor (igf-i) Expired - Lifetime EP1456182B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SI200230824T SI1456182T1 (en) 2001-12-07 2002-12-03 Pyrimidine derivatives as modulators of insuline-like growth factor-1 receptor (igf-i)
CY20091100558T CY1109101T1 (en) 2001-12-07 2009-05-25 PYRIMIDINE PRODUCTS AS REGULATORY RECEPTORS (IGF-I) INSULINUS GROWTH FACTOR-1

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE0104140 2001-12-07
SE0104140A SE0104140D0 (en) 2001-12-07 2001-12-07 Novel Compounds
PCT/SE2002/002221 WO2003048133A1 (en) 2001-12-07 2002-12-03 Pyrimidine derivatives as modulators of insuline-like growth factor-1 receptor (igf-i)

Publications (2)

Publication Number Publication Date
EP1456182A1 EP1456182A1 (en) 2004-09-15
EP1456182B1 true EP1456182B1 (en) 2009-03-11

Family

ID=20286257

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02791165A Expired - Lifetime EP1456182B1 (en) 2001-12-07 2002-12-03 Pyrimidine derivatives as modulators of insuline-like growth factor-1 receptor (igf-i)

Country Status (33)

Country Link
US (3) US7521453B2 (en)
EP (1) EP1456182B1 (en)
JP (1) JP4347051B2 (en)
KR (1) KR100930558B1 (en)
CN (1) CN1289486C (en)
AR (1) AR037736A1 (en)
AT (1) ATE425150T1 (en)
AU (1) AU2002365864B2 (en)
BR (1) BR0214605A (en)
CA (1) CA2467838C (en)
CO (1) CO5590919A2 (en)
CY (1) CY1109101T1 (en)
DE (1) DE60231542D1 (en)
DK (1) DK1456182T3 (en)
EG (1) EG24930A (en)
ES (1) ES2323125T3 (en)
HK (1) HK1067631A1 (en)
HU (1) HUP0401855A3 (en)
IL (2) IL162376A0 (en)
IS (1) IS7294A (en)
MX (1) MXPA04005347A (en)
MY (1) MY135705A (en)
NO (1) NO327502B1 (en)
NZ (1) NZ533130A (en)
PL (1) PL369528A1 (en)
PT (1) PT1456182E (en)
RU (1) RU2317291C2 (en)
SE (1) SE0104140D0 (en)
SI (1) SI1456182T1 (en)
TW (1) TWI324152B (en)
UA (1) UA78259C2 (en)
WO (1) WO2003048133A1 (en)
ZA (1) ZA200404223B (en)

Families Citing this family (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0104140D0 (en) * 2001-12-07 2001-12-07 Astrazeneca Ab Novel Compounds
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
ATE451104T1 (en) 2002-07-29 2009-12-15 Rigel Pharmaceuticals Inc METHOD FOR TREATING OR PREVENTING AUTOIMMUNE DISEASES USING 2,4-PYRIMIDINEDIAMINE COMPOUNDS
US7504396B2 (en) 2003-06-24 2009-03-17 Amgen Inc. Substituted heterocyclic compounds and methods of use
US7442698B2 (en) 2003-07-24 2008-10-28 Amgen Inc. Substituted heterocyclic compounds and methods of use
PL1656372T3 (en) 2003-07-30 2013-08-30 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases
US20050113398A1 (en) * 2003-08-07 2005-05-26 Ankush Argade 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
WO2005037836A2 (en) * 2003-10-15 2005-04-28 Osi Pharmaceuticals, Inc. Imidazo ‘1, 5 - a ! pyrazine tyrosine kinase inhibitors
DE602004022187D1 (en) 2003-10-17 2009-09-03 Astrazeneca Ab 4- (PYRAZOL-3-YLAMINO) PYRIMIDINE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER
MY141220A (en) * 2003-11-17 2010-03-31 Astrazeneca Ab Pyrazole derivatives as inhibitors of receptor tyrosine kinases
SI1732898T1 (en) 2004-03-12 2008-06-30 Analytecon Sa Tetrahydroisoquinoline- and tetrahydrobenzazepine derivatives as igf-1r inhibitors
EP1730128A1 (en) * 2004-03-31 2006-12-13 Exelixis, Inc. Anaplastic lymphoma kinase modulators and methods of use
DK1740591T3 (en) * 2004-04-02 2009-10-26 Osi Pharm Inc Heterobicyclic protein kinase inhibitors substituted with a 6,6-biocyclic ring
DE102004022897A1 (en) * 2004-05-10 2005-12-08 Bayer Cropscience Ag Azinyl-imidazoazines
TW200613306A (en) 2004-07-20 2006-05-01 Osi Pharm Inc Imidazotriazines as protein kinase inhibitors
US7557207B2 (en) 2004-11-24 2009-07-07 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
ATE519759T1 (en) * 2004-12-30 2011-08-15 Exelixis Inc PYRIMIDINE DERIVATIVES AS KINASE MODULATORS AND METHODS OF APPLICATION
BRPI0606318B8 (en) 2005-01-19 2021-05-25 Rigel Pharmaceuticals Inc compound, composition, and use of a compound
ES2375735T3 (en) 2005-02-04 2012-03-05 Astrazeneca Ab USEFUL PIRAZOLILAMINOPIRIDINE DERIVATIVES AS QUINASE INHIBITORS.
AU2006215386B2 (en) 2005-02-16 2009-06-11 Astrazeneca Ab Chemical compounds
GB0507347D0 (en) * 2005-04-12 2005-05-18 Astrazeneca Ab Chemical compounds
CN101208093A (en) * 2005-04-27 2008-06-25 阿斯利康(瑞典)有限公司 Use of pyrazolyl-pyrimidine derivatives in the treatment of pain
BRPI0610184A2 (en) * 2005-05-16 2012-09-25 Astrazeneca Ab compound, pharmaceutically acceptable salt of a compound, process for preparing a compound or a pharmaceutically acceptable salt thereof, use of a compound or a pharmaceutically acceptable salt thereof, methods for inhibiting trk activity, for cancer treatment or prophylaxis and for producing an antiproliferative effect on a warm-blooded animal, and, pharmaceutical composition
WO2006133426A2 (en) 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US20070203161A1 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US7566721B2 (en) * 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
CA2620174A1 (en) 2005-08-24 2007-03-01 Wyeth Bazedoxifene acetate formulations and manufacturing process thereof
WO2007035744A1 (en) 2005-09-20 2007-03-29 Osi Pharmaceuticals, Inc. Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
EP2388259A1 (en) * 2005-10-28 2011-11-23 AstraZeneca AB 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer
AR057960A1 (en) 2005-12-02 2007-12-26 Osi Pharm Inc BICYCLE PROTEIN QUINASE INHIBITORS
US8575164B2 (en) * 2005-12-19 2013-11-05 OSI Pharmaceuticals, LLC Combination cancer therapy
UA97953C2 (en) * 2006-06-09 2012-04-10 Новартіс Аг Stabilized insulin-like growth factor polypeptides
AU2007257701A1 (en) * 2006-06-15 2007-12-21 Boehringer Ingelheim International Gmbh 2-anilino-4-aminoalkyleneaminopyrimidines
TW200817391A (en) * 2006-06-30 2008-04-16 Astrazeneca Ab Novel compounds
EP2043651A2 (en) * 2006-07-05 2009-04-08 Exelixis, Inc. Methods of using igf1r and abl kinase modulators
WO2008129255A1 (en) * 2007-04-18 2008-10-30 Astrazeneca Ab 5-aminopyrazol-3-yl-3h-imidazo [4,5-b] pyridine derivatives and their use for the treatment of cancer
US20100204231A1 (en) * 2007-05-04 2010-08-12 Astrazeneca Ab Amino-thiazolyl-pyrimidine derivatives and their use for the treatment of cancer
UA99459C2 (en) * 2007-05-04 2012-08-27 Астразенека Аб 9-(pyrazol-3-yl)- 9h-purine-2-amine and 3-(pyraz0l-3-yl)-3h-imidazo[4,5-b]pyridin-5-amine derivatives and their use for the treatment of cancer
US8178091B2 (en) 2007-05-21 2012-05-15 University Of Washington Compositions and methods for the treatment of respiratory disorders
WO2009019518A1 (en) * 2007-08-09 2009-02-12 Astrazeneca Ab Pyrimidine compounds having a fgfr inhibitory effect
WO2009091939A1 (en) * 2008-01-18 2009-07-23 Osi Pharmaceuticals, Inc. Imidazopyrazinol derivatives for the treatment of cancers
JP2011520970A (en) * 2008-05-19 2011-07-21 オーエスアイ・フアーマスーテイカルズ・インコーポレーテツド Substituted imidazopyrazines and imidazotriazines
CA2727073A1 (en) * 2008-06-11 2009-12-17 Astrazeneca Ab Tricyclic 2,4-diamin0-l,3,5-triazine derivatives useful for the treatment of cancer and myeloproliferative disorders
DE102008041214A1 (en) 2008-08-13 2010-02-18 Bayer Cropscience Ag New N-substituted azinylalkyl-azincarboxamide compounds useful e.g. in plant protection, for combating animal pests, arthropods, nematodes and plant diseases, and for protecting industrial materials against attack and destruction by insect
KR20110071098A (en) * 2008-09-30 2011-06-28 아스트라제네카 아베 Heterocyclic jak kinase inhibitors
US20120189641A1 (en) 2009-02-25 2012-07-26 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
EP2400990A2 (en) 2009-02-26 2012-01-04 OSI Pharmaceuticals, LLC In situ methods for monitoring the emt status of tumor cells in vivo
WO2010099138A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
EP2401614A1 (en) 2009-02-27 2012-01-04 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
US8465912B2 (en) 2009-02-27 2013-06-18 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
MX2011011025A (en) 2009-04-20 2011-11-02 Osi Pharmaceuticals Llc Preparation of c-pyrazine-methylamines.
WO2010129740A1 (en) * 2009-05-07 2010-11-11 Osi Pharmaceuticals, Inc. Use of osi-906 for treating adrenocortical carcinoma
WO2010146059A2 (en) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarkers for igf-1r inhibitor therapy
WO2011109584A2 (en) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
US20110275644A1 (en) 2010-03-03 2011-11-10 Buck Elizabeth A Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
EP2544672A1 (en) 2010-03-09 2013-01-16 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
CN102970867A (en) 2010-03-18 2013-03-13 拜耳知识产权有限责任公司 Aryl and hetaryl sulfonamides as active agents against abiotic plant stress
KR20130031296A (en) 2010-05-21 2013-03-28 케밀리아 에이비 Novel pyrimidine derivatives
US8546443B2 (en) * 2010-12-21 2013-10-01 Boehringer Ingelheim International Gmbh Benzylic oxindole pyrimidines
WO2012106556A2 (en) 2011-02-02 2012-08-09 Amgen Inc. Methods and compositons relating to inhibition of igf-1r
US20120214830A1 (en) 2011-02-22 2012-08-23 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors in hepatocellular carcinoma
DK2688883T3 (en) 2011-03-24 2016-09-05 Noviga Res Ab pyrimidine
US8729253B2 (en) 2011-04-13 2014-05-20 Eastman Chemical Company Cellulose ester optical films
US9896730B2 (en) 2011-04-25 2018-02-20 OSI Pharmaceuticals, LLC Use of EMT gene signatures in cancer drug discovery, diagnostics, and treatment
WO2013071056A2 (en) 2011-11-11 2013-05-16 Duke University Combination drug therapy for the treatment of solid tumors
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
US8980259B2 (en) 2012-07-20 2015-03-17 Novartis Ag Combination therapy
JP6255038B2 (en) 2013-02-26 2017-12-27 トリアクト セラピューティクス，インク． Cancer treatment
EP3044593A4 (en) 2013-09-09 2017-05-17 Triact Therapeutics, Inc. Cancer therapy
WO2017129763A1 (en) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer
CN115124475B (en) * 2022-07-11 2023-11-10 贵阳学院 Pyrimidine derivative and preparation method and application thereof
WO2024153237A1 (en) * 2023-01-19 2024-07-25 北京普祺医药科技股份有限公司 Igf-1r tyrosine kinase inhibitors, pharmaceutical composition and use thereof

Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1417402A (en) * 1972-03-30 1975-12-10 Boots Co Ltd Pharmacologically active anilinobenzothiazoles
DE2426180A1 (en) 1974-05-29 1975-12-18 Bayer Ag METHOD OF COLORING POLYURETHANE PLASTICS
US4485284A (en) * 1982-01-11 1984-11-27 Advanced Moisture Technology, Inc. Apparatus and process for microwave moisture analysis
HU206337B (en) 1988-12-29 1992-10-28 Mitsui Petrochemical Ind Process for producing pyrimidine derivatives and pharmaceutical compositions
US5521184A (en) * 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
CA2104053C (en) * 1992-08-31 1999-04-13 Miguel A. Cacho Automated fluid bed process
WO1997009325A1 (en) 1995-09-01 1997-03-13 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
US5935966A (en) 1995-09-01 1999-08-10 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
GB9523675D0 (en) 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
EP0970369B1 (en) * 1997-03-27 2001-09-12 Glatt Gmbh Method for monitoring and/or controlling and regulating a granulation, agglomeration, instantization, coating and drying process in a fluidized layer or a fluidized bed by determining product moisture, and device for carrying out said method
US6247246B1 (en) * 1998-05-27 2001-06-19 Denver Instrument Company Microwave moisture analyzer: apparatus and method
AU5438299A (en) 1998-08-29 2000-03-21 Astrazeneca Ab Pyrimidine compounds
KR100658489B1 (en) 1998-11-10 2006-12-18 얀센 파마슈티카 엔.브이. HIV replication inhibiting pyrimidines
WO2000035455A1 (en) 1998-12-15 2000-06-22 Telik, Inc. Heteroaryl-aryl ureas as igf-1 receptor antagonists
GB9828511D0 (en) * 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
DE19917785A1 (en) 1999-04-20 2000-10-26 Bayer Ag New 2,4-diamino-pyrimidine derivatives useful as microbicides in protection of plants and materials and as herbicides
GB9914258D0 (en) 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
US6399780B1 (en) * 1999-08-20 2002-06-04 Cephalon, Inc. Isomeric fused pyrrolocarbazoles and isoindolones
JP4919566B2 (en) * 1999-09-24 2012-04-18 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Antiviral composition
US6455525B1 (en) * 1999-11-04 2002-09-24 Cephalon, Inc. Heterocyclic substituted pyrazolones
HUP0301117A3 (en) 2000-02-17 2004-01-28 Amgen Inc Thousand Oaks Imidazole derivatives kinase inhibitors, their use, process for their preparation and pharmaceutical compositions containing them
GB0004887D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004890D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
EP1282607B1 (en) 2000-05-08 2015-11-11 Janssen Pharmaceutica NV Prodrugs of hiv replication inhibiting pyrimidines
JP4105948B2 (en) 2000-09-15 2008-06-25 バーテックス ファーマシューティカルズ インコーポレイテッド Pyrazole compounds useful as protein kinase inhibitors
US6660731B2 (en) * 2000-09-15 2003-12-09 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7473691B2 (en) * 2000-09-15 2009-01-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6610677B2 (en) * 2000-09-15 2003-08-26 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6613776B2 (en) * 2000-09-15 2003-09-02 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
KR100909665B1 (en) 2000-12-21 2009-07-29 버텍스 파마슈티칼스 인코포레이티드 Pyrazole Compounds Useful as Protein Kinase Inhibitors and Pharmaceutical Compositions Comprising the Same
JP4357295B2 (en) * 2001-08-03 2009-11-04 バーテックス ファーマシューティカルズ インコーポレイテッド Pyrazole-induced kinase inhibitors and uses thereof
WO2003011854A1 (en) * 2001-08-03 2003-02-13 Vertex Pharmaceuticals Incorporated Pyrazole-derived kinase inhibitors and uses thereof
US6747461B2 (en) * 2001-10-25 2004-06-08 Pioneer Hi-Bred International, Inc. Apparatus and method for monitoring drying of an agricultural porous medium such as grain or seed
SE0104140D0 (en) * 2001-12-07 2001-12-07 Astrazeneca Ab Novel Compounds
MY141220A (en) * 2003-11-17 2010-03-31 Astrazeneca Ab Pyrazole derivatives as inhibitors of receptor tyrosine kinases
CA2586375A1 (en) * 2004-11-04 2006-05-18 Juan-Miguel Jimenez Pyrazolo[1,5-a]pyrimidines useful as inhibitors of protein kinases
AU2006215386B2 (en) * 2005-02-16 2009-06-11 Astrazeneca Ab Chemical compounds
ES2533241T3 (en) * 2005-11-03 2015-04-08 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
TW200817391A (en) * 2006-06-30 2008-04-16 Astrazeneca Ab Novel compounds
TW200826937A (en) * 2006-11-01 2008-07-01 Astrazeneca Ab New use
TW200823196A (en) * 2006-11-01 2008-06-01 Astrazeneca Ab New use

Also Published As

Publication number Publication date
EP1456182A1 (en) 2004-09-15
IL162376A0 (en) 2005-11-20
AU2002365864B2 (en) 2007-08-30
KR100930558B1 (en) 2009-12-09
TWI324152B (en) 2010-05-01
WO2003048133A1 (en) 2003-06-12
NO327502B1 (en) 2009-07-27
US20050054638A1 (en) 2005-03-10
CA2467838A1 (en) 2003-06-12
CO5590919A2 (en) 2005-12-30
TW200409634A (en) 2004-06-16
MXPA04005347A (en) 2004-09-27
ZA200404223B (en) 2005-08-29
MY135705A (en) 2008-06-30
EG24930A (en) 2011-01-11
UA78259C2 (en) 2007-03-15
NO20042872L (en) 2004-07-06
NZ533130A (en) 2006-11-30
SI1456182T1 (en) 2009-08-31
KR20050044698A (en) 2005-05-12
CA2467838C (en) 2010-10-12
JP4347051B2 (en) 2009-10-21
AR037736A1 (en) 2004-12-01
HUP0401855A2 (en) 2004-12-28
US7521453B2 (en) 2009-04-21
RU2004121029A (en) 2006-01-10
BR0214605A (en) 2004-09-14
CN1617858A (en) 2005-05-18
DE60231542D1 (en) 2009-04-23
ES2323125T3 (en) 2009-07-07
HUP0401855A3 (en) 2008-06-30
US20120095011A1 (en) 2012-04-19
IL162376A (en) 2011-07-31
US20090131463A1 (en) 2009-05-21
SE0104140D0 (en) 2001-12-07
JP2005515998A (en) 2005-06-02
PL369528A1 (en) 2005-05-02
CN1289486C (en) 2006-12-13
RU2317291C2 (en) 2008-02-20
IS7294A (en) 2004-06-03
DK1456182T3 (en) 2009-06-29
CY1109101T1 (en) 2014-07-02
AU2002365864A1 (en) 2003-06-17
HK1067631A1 (en) 2005-04-15
ATE425150T1 (en) 2009-03-15
PT1456182E (en) 2009-05-26

Similar Documents

Publication Publication Date Title
EP1456182B1 (en) Pyrimidine derivatives as modulators of insuline-like growth factor-1 receptor (igf-i)
EP1678169B1 (en) 4-(pyrazol-3-ylamino)pyrimidine derivatives for use in the treatment of cancer
AU2005315392B2 (en) 4- (4- (imidazol-4-yl) pyrimidin-2-ylamino) benzamides as CDK inhibitors
EP2044051B1 (en) Pyridine and pyrazine derivatives as mnk kinase inhibitors
EP2048142A2 (en) Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof
TW200403060A (en) Inhibitors of tyrosine kinases
MX2008016523A (en) Pyrimidine derivatives useful in the treatment of cancer.
KR20050042478A (en) Protein kinase inhibitors and uses thereof
WO2007031745A1 (en) Pyrimidine derivatives for the inhibition of igf-ir tyrosine kinase activity
EP1869032B1 (en) Pyrimidine derivatives for use as anticancer agents
JP2008534661A (en) Pyrimidines as IGF-1 inhibitors
EP2029543B1 (en) Substituted 3-cyanopyridines as protein kinase inhibitors
EP4206196A1 (en) Pyrimidine substituted derivatives as tyk2 inhibitors
CN101184752A (en) Pyrimidine derivatives for use as anticancer agents
MXPA06004277A (en) 4-(pyrazol-3-ylamino) pyrimidine derivatives for use in the treatment of cancer
WO2014178381A1 (en) Pharmaceutical composition for the treatment of diabetes

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040707

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1067631

Country of ref document: HK

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60231542

Country of ref document: DE

Date of ref document: 20090423

Kind code of ref document: P

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20090520

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2323125

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20090401409

Country of ref document: GR

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1067631

Country of ref document: HK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20091214

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20101122

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20111124

Year of fee payment: 10

Ref country code: FI

Payment date: 20111201

Year of fee payment: 10

Ref country code: LU

Payment date: 20111219

Year of fee payment: 10

Ref country code: IE

Payment date: 20111128

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20120103

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BG

Payment date: 20121029

Year of fee payment: 11

Ref country code: MC

Payment date: 20121109

Year of fee payment: 11

Ref country code: DE

Payment date: 20121128

Year of fee payment: 11

Ref country code: CZ

Payment date: 20121127

Year of fee payment: 11

Ref country code: EE

Payment date: 20121116

Year of fee payment: 11

Ref country code: CH

Payment date: 20121213

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SK

Payment date: 20121123

Year of fee payment: 11

Ref country code: GR

Payment date: 20121115

Year of fee payment: 11

Ref country code: ES

Payment date: 20121227

Year of fee payment: 11

Ref country code: GB

Payment date: 20121128

Year of fee payment: 11

Ref country code: SI

Payment date: 20121119

Year of fee payment: 11

Ref country code: PT

Payment date: 20120604

Year of fee payment: 11

Ref country code: IT

Payment date: 20121110

Year of fee payment: 11

Ref country code: SE

Payment date: 20121217

Year of fee payment: 11

Ref country code: TR

Payment date: 20121112

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20130107

Year of fee payment: 11

Ref country code: NL

Payment date: 20121215

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20121114

Year of fee payment: 11

BERE Be: lapsed

Owner name: ASTRAZENECA A.B.

Effective date: 20121231

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 425150

Country of ref document: AT

Kind code of ref document: T

Effective date: 20121203

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121203

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121203

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121203

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130102

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121203

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20140603

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60231542

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20140701

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM9D

Effective date: 20131203

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131231

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E003319

Country of ref document: EE

Effective date: 20131231

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20131203

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140603

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131204

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131204

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131203

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20140710

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20090401409

Country of ref document: GR

Effective date: 20140702

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 5703

Country of ref document: SK

Effective date: 20131203

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20140829

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60231542

Country of ref document: DE

Effective date: 20140701

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140701

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131203

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140702

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131231

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140701

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131231

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140930

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131203

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131231

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131203

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20150327

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131204

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131203

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131203